
==== Front
Cell Res
Cell Res
Cell Research
1001-0602
1748-7838
Springer Nature Singapore Singapore

39054345
975
10.1038/s41422-024-00975-8
Review Article
Coding, or non-coding, that is the question
http://orcid.org/0000-0001-6557-955X
Poliseno Laura laura.poliseno@cnr.it

12
http://orcid.org/0009-0004-1384-615X
Lanza Martina 123
http://orcid.org/0000-0002-5352-5295
Pandolfi Pier Paolo pierpaolo.pandolfiderinaldis@unito.it

45
1 Oncogenomics Unit, Core Research Laboratory, ISPRO, Pisa, Italy
2 https://ror.org/01kdj2848 grid.418529.3 0000 0004 1756 390X Institute of Clinical Physiology, CNR, Pisa, Italy
3 https://ror.org/01tevnk56 grid.9024.f 0000 0004 1757 4641 University of Siena, Siena, Italy
4 https://ror.org/048tbm396 grid.7605.4 0000 0001 2336 6580 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy
5 https://ror.org/03sxdvx36 grid.298261.6 0000 0000 8685 5368 Renown Institute for Cancer, Nevada System of Higher Education, Reno, NV USA
25 7 2024
25 7 2024
9 2024
34 9 609629
3 1 2024
30 4 2024
© The Author(s) 2024
2024
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The advent of high-throughput sequencing uncovered that our genome is pervasively transcribed into RNAs that are seemingly not translated into proteins. It was also found that non-coding RNA transcripts outnumber canonical protein-coding genes. This mindboggling discovery prompted a surge in non-coding RNA research that started unraveling the functional relevance of these new genetic units, shaking the classic definition of “gene”. While the non-coding RNA revolution was still taking place, polysome/ribosome profiling and mass spectrometry analyses revealed that peptides can be translated from non-canonical open reading frames. Therefore, it is becoming evident that the coding vs non-coding dichotomy is way blurrier than anticipated. In this review, we focus on several examples in which the binary classification of coding vs non-coding genes is outdated, since the same bifunctional gene expresses both coding and non-coding products. We discuss the implications of this intricate usage of transcripts in terms of molecular mechanisms of gene expression and biological outputs, which are often concordant, but can also surprisingly be discordant. Finally, we discuss the methodological caveats that are associated with the study of bifunctional genes, and we highlight the opportunities and challenges of therapeutic exploitation of this intricacy towards the development of anticancer therapies.

Subject terms

Cancer models
Targeted therapies
Mechanisms of disease
Transcription
Translation
ISPRO-Istituto per lo Studio, la Prevenzione e la Rete Oncologica AIRC-Associazione Italiana per la Ricerca sul CancroRenown Foundation PTEN Research Foundationissue-copyright-statement© Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences 2024
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pmcIntroduction

In his article published in Nature in 1970, Francis Crick stated the central dogma of molecular biology: information is passed from DNA (gene) to protein, through messenger RNA (mRNA).1 Approximately 50 years later, the central dogma still stands. However, it has become just one among many mechanisms through which functional molecules are expressed from our genome.2

Over the years it has become more and more evident that our genomic DNA is pervasively transcribed. The portion transcribed into mRNAs, which in turn are translated into ∼20,000 proteins, is minimal (2%–5%). Far from being “junk DNA”, most of the rest (75%–90%) is rather transcribed into hundreds of thousands of non-coding RNAs (ncRNAs)3 that are emerging as sophisticated regulators of gene expression. Together with proteins, they govern embryonic development,4,5 maintain the physiological state,6 define organism complexity,3,7 and are causally linked with hereditary and non-hereditary diseases,8,9 including cancer.5,10

According to their function, ncRNAs are classified into housekeeping ncRNAs and regulatory ncRNAs. Housekeeping ncRNAs (ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs)) were the first ncRNAs to be identified and studied. They are up to ~4.5 kb long and ubiquitously expressed, as they are involved in essential processes for cell survival. Specifically, rRNAs and tRNAs reside in the cytoplasm and are core components of the mechanism of protein translation. rRNAs represent the RNA component of ribosomes, while tRNAs act as adaptors between the mRNA and amino acids. snRNAs and snoRNAs are instead located in the nucleus. snRNAs represent the RNA component of spliceosomes. snoRNAs represent the RNA component of small nucleolar ribonucleoprotein particles (snoRNPs), which are responsible for maturation of pre-rRNAs through nucleoside modifications (mainly methylation and pseudouridylation).11,12 Interestingly, examples are accumulating of rRNAs, tRNAs, snRNAs, and snoRNAs with an oncogenic or tumor-suppressive role in human cancer, precisely because they regulate core mechanisms of gene expression. They are also explored as diagnostic and prognostic biomarkers.13–15

Regulatory ncRNAs are further divided according to their lengths. Among short ncRNAs (< 200 nt) there are PIWI-interacting RNAs16 and microRNAs (miRNAs). Long ncRNAs (lncRNAs, ≥ 500 nt) include long intergenic non-coding RNAs (lincRNAs), pseudogenic RNAs (PGs), Natural Antisense Transcripts (NATs), and circular RNAs (circRNAs).5 The expression of regulatory ncRNAs is tightly controlled, they perform a range of functions that is as wide as that performed by proteins, and their dysregulation has been linked to many pathological conditions, including cancer.

miRNAs are 19–25-nt short ncRNAs that inhibit gene expression at post-transcriptional level. The human genome contains hundreds of miRNAs (https://mirbase.org/). Primary miRNAs (pri-miRNAs) are transcribed and processed (first in the nucleus, then in the cytoplasm) to precursor miRNAs (pre-miRNAs) and finally to single-strand mature miRNAs, which recruit the Argonaute (AGO) protein to form the miRNA-induced silencing complex (miRISC).10 miRISC binds target RNAs in correspondence of specific sequences termed miRNA Recognition Elements (MREs). The result is a decrease in target expression through RNA degradation or translational repression. Each miRNA recognizes hundreds of targets, and each target can be recognized by multiple miRNAs. Therefore, most miRNAs are soft and pervasive tuners of gene expression.17–19 In addition, as described in “Translation of pri-miRNAs” chapter below, examples exist of miRNA precursors that are translated into functional peptides.

In cancer, miRNA expression and sequence are altered,20 and, depending on the repressed targets, they act as oncogenes (oncomiRs) or as tumor suppressors.21–23 Interestingly, there are cases in which the same miRNA behaves as oncogene in some cancer types and tumor suppressor in other cancer types. This attests the pervasive nature of miRNA-mediated regulation of gene expression, with net results depending on the balance among all targets at play.24 miRNAs are also extensively used as diagnostic, prognostic, and predictive biomarkers. Since they can be detected in body fluids such as blood, saliva and urine, circulating miRNAs represent in fact a much less invasive alternative to the classic biopsy.25–27 Finally, they are exploited therapeutically (inhibition of oncomiRs and replacement of tumor-suppressive miRNAs).28

Relevant to the topic of this review, we discovered a new mechanism for the regulation of miRNA activity: miRNAs are negative regulators of target RNA expression, but in turn target RNAs are negative regulators of miRNA function. This is because they compete for binding to common miRNAs, i.e., they act as competing endogenous RNAs (ceRNAs). ceRNA partners that share MRE(s) for the same miRNA(s) dilute the miRNA(s), blunting their efficacy and at the same time sustaining their own expression.29 ceRNA-based regulation can occur only if some conditions are satisfied: ceRNA partners and the shared miRNA(s) need to be present in the same subcellular compartment and to be expressed at similar level. Furthermore, the sponging effect gets stronger at the increase of the number and the affinity of shared MREs.30–38 Experimental evidence indicate that ceRNA-based regulation is common among coding (see “The 3′UTR exerts non-coding functions” chapter below) and all classes of non-coding RNAs. Furthermore, it can produce extended networks, which get heavily disrupted in cancer.39–47

The human genome contains more than 30,000 lncRNA genes, which are expressed into more than 100 thousand transcripts (https://www.gencodegenes.org/human/stats_45.html5,48). Although the mechanism of transcription initiation and termination can be different from those of mRNAs,49 most lncRNAs are transcribed by Pol II. Nevertheless, examples exist of lncRNAs transcribed by Pol I or Pol III. Furthermore, many lncRNAs undergo splicing, but they can be transcribed from single-exon genes as well.50 Analogously, they may or may not undergo 5′ capping and 3′ polyadenynation.5 Besides transcription mechanisms, heterogeneity extends to many other features of lncRNAs. According to the position of their genes, they are grouped into lincRNAs, intronic lncRNAs or pseudogenes, while according to the direction of their transcription they are divided into sense transcripts and NATs. Furthermore, all lncRNAs are linear transcripts, except for circRNAs, while subcellular localization defines nuclear vs cytoplasmatic lncRNAs.5,51

To date, just a small fraction of all lncRNAs have been studied, and what we already know might just be the tip of the iceberg. In any case, they appear as flexible molecules that organize in thermodynamically-stable secondary or even higher-order structures. Acting as signals, guides, decoys, or scaffolds, they regulate virtually each step of gene expression: nuclear organization and genome integrity, chromatin remodeling by epigenetic modification, transcription, RNA splicing and processing, mRNA stability and translation, protein post-translational modification (e.g., phosphorylation), subcellular localization, and activity.5,52–55

lncRNAs are altered in cancer and, depending on their mechanisms of action and on the effectors involved, they can act either as oncogenes or as tumor suppressors. Furthermore, in the last few years lncRNAs have taken center stage as diagnostic, prognostic and predictive biomarkers. Crucially, oncogenic lncRNAs are currently explored as therapeutic targets, using approaches based on antisense oligonucleotides, RNA interference, or CRISPR/Cas9 technology.56,57 Furthermore, lncRNAs encoding tumor-specific antigens can be exploited as anticancer vaccines.58

Among linear lncRNAs, lincRNAs are the most conspicuous group and include some of the most well-studied examples, in development and in cancer.59 LincRNA X-inactive specific transcript (Xist), which is responsible for X chromosome inactivation and gene dosage compensation, was discovered in the early 90s and is the first long non-coding RNA to be ever studied.60 Fifteen years later, HOX antisense intergenic RNA (HOTAIR) was discovered. This lincRNA is transcribed from an independent promoter located in antisense strand within the HOXC locus, and it causes epigenetic silencing of the HOXD locus.61 In cancer, examples of well-studied lincRNAs include: BRAF-Activated Non-protein Coding RNA (BANCR62), linc-Regulator Of Reprogramming (linc-RoR63), Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT-150), and Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON64). These are pleiotropic lincRNAs that exert oncogenic functions in multiple cancer types by affecting key cellular processes (motility, stemness, chemosensitivity, and mitochondrial metabolism, respectively). Mechanistically, lincRNAs have the activities listed above for lncRNA. Interestingly, they can also be translated into functional peptides, as we describe in “Translation of lincRNAs” chapter below.

A group of linear lncRNAs with peculiar features is represented by NATs. The development of high-throughput sequencing has shed light on this class of RNA molecules that are transcribed from the opposite DNA strand. They originate from bidirectional promoters shared with the corresponding sense transcripts, from independent antisense promoters, or from latent antisense promoters located within sense transcriptional units. According to the degree of overlap with sense transcripts, NATs are defined as head-to-head (the overlap is in the 5′ region), tail-to-tail (the overlap is in the 3′ region) or embedded (the overlap is complete). Finally, cis-NATs exert their function on their own genomic locus, while trans-NATs act on other genomic loci. In cancer, several NATs are known to be involved in the regulation of gene expression at multiple levels: in the nucleus, epigenetic modification, transcription, RNA splicing and processing; in the cytoplasm, mRNA stability and translation, post-translational modification of proteins. As such, they play oncogenic or tumor-suppressive roles and they are highly valued as diagnostic, prognostic, and predictive biomarkers.65,66

Another group of linear lncRNAs with peculiar features is represented by pseudogenes. With the name “pseudogene” we refer to a region of the genome that contains a defective copy of a parental protein-coding gene. Indeed, pseudogenes are characterized by the presence of mutations, deletions or insertions that lead to frameshifts and prevent translation of parental protein products. The human genome contains ∼14,000 pseudogenes, 10% of which are transcribed (https://www.gencodegenes.org/human/stats_45.html67).

According to their origin, pseudogenes are classified as follows. Processed pseudogenes, which represent the most abundant class, derive from a retrotransposition event. They do not contain introns, are located on different chromosomes compared to parental genes, and are subjected to a distinct regulation of gene expression. They accumulate alterations because retrotranscription is error prone. Nonprocessed pseudogenes derive from gene duplication. They are located on the same chromosome as parental genes and retain introns, as well as regulatory regions (promoter). They accumulate alterations because the sequence of the parental copy is the only one preserved under selective pressure. Finally, unitary pseudogenes arise from the accumulation of alterations in an ancestral protein-coding gene that has no other copy in the genome.68,69

Even though they have been considered functionless for a long time, in the recent years we and others have contributed to discovering that pseudogenes exert a wide range of parental gene-related as well as parental gene-unrelated functions. Specifically, PGs are involved in chromatin remodeling, sponging of miRNAs and RNA Binding Proteins (RBPs), and mRNA degradation through endosiRNAs.68,70–74 As described in “Translation of PGs” chapter below, they are also translated into functional peptides and proteins.

The contribution of pseudogenes to cancer initiation and progression is gaining momentum. There are in fact several examples of oncogenic and tumor-suppressive pseudogenes.69 Interestingly, with their random “landing” upon retrotranscription, processed pseudogenes acquired somatically can potentially disrupt otherwise functional genetic units and therefore can be considered mutagenic factors.75 PGs are also highly valuable as diagnostic and prognostic biomarkers.76 Oncogenic PGs are explored as therapeutic targets,77,78 while PGs that act as sponges of oncogenic miRNAs are envisioned as drugs.73 Finally, PGs that encode immunogenic peptides could reveal effective as anticancer vaccines.73,79

The ∼25,000 circRNAs constitute the group of non-linear lncRNAs.80 circRNAs are single-stranded, covalently-closed RNA molecules characterized by high stability since they are immune from exonucleases activity. circRNAs are mostly generated by back-splicing of pre-mRNAs. Contrary to canonical splicing in which an upstream 5′ splice donor is joined with a downstream 3′ splice acceptor, back-splicing is an unconventional splicing event in which an upstream 3′ splice acceptor is joined with a 5′ downstream splice donor, leading to the formation of a circular-shaped structure. As a result of this peculiar splicing mechanism, circRNAs are classified as follows. Exonic circRNAs (EcircRNAs) are composed entirely by exons. They are the largest subclass of circRNAs (they account for ∼85% of all circRNAs) and are mainly located in the cytoplasm. Conversely, Exonic-Intronic circRNAs (EIcircRNAs) are composed both by exons and by introns and are mainly retained in the nucleus. In alternative to back-splicing, circRNAs can also originate from lariat introns that fail to undergo debranching and are subsequently subjected to trimming of the lariat tail. Because of such biogenesis, circular intronic RNAs (ciRNAs) are composed only by introns and are mainly retained in the nucleus.81

The molecular functions attributed to circRNAs are in line with their subcellular localization. Nuclear EIcircRNAs and ciRNAs mainly act in cis as regulators of transcription or splicing of their own gene. Conversely, cytoplasmic EcircRNAs mainly act in trans: as sponges for miRNAs and for RBPs, they play a crucial role in the post-transcriptional regulation of gene expression; they form circRNPs that modulate signaling pathways; as described in “Translation of circRNAs” chapter below, they can also be translated into functional peptides.82,83

There are several examples of oncogenic or tumor-suppressive circRNAs in cancer.84 They have gained attention in the context of resistance to traditional chemotherapeutic drugs, as well as targeted and immunotherapy approaches.85,86 Extensively studied as diagnostic, prognostic, and predictive biomarkers,83,87 circRNAs are the focus of many therapeutic strategies as well. Oncogenic circRNAs are targeted through antisense oligonucleotides, RNA interference, or CRISPR/Cas9 technology. In addition, their exceedingly high stability has prompted testing of circRNAs as drugs: synthetically engineered circRNAs are currently under evaluation as sponges for oncogenic miRNAs,83,87,88 while circRNAs encoding tumor-specific antigens can be envisioned as anticancer vaccines.89,90

Still overwhelmed by the discovery of pervasive genome transcription, in the most recent years we have been hit by a counter-wave of pervasive translation. In the last decades, the ∼20,000 proteins encoded by our genome (https://www.gencodegenes.org/human/stats_45.html) have been the undivided focus of cancer research. The most potent oncogenes and tumor suppressors known so far (e.g., BRAF and c-MYC vs p53 and PTEN) are in fact proteins. They have almost completely monopolized in vivo cancer modeling,91 and they are the targets of most of the current anticancer therapies, using synthetic small molecules92 or even other proteins (e.g., antibodies93). Considering the profound and vast knowledge on protein medicinal chemistry that we have accumulated, the recent discovery that several ncRNAs can be translated into peptides was good news to many. Even more recently, additional open reading frames (ORFs) have been found to reside within the 5′ untranslated region (UTR) of hundreds of mRNAs. These “upstream ORFs (uORFs)” are short and contribute to regulating the translation of the longer coding sequences (CDSs) located downstream.94–98

With this mindboggling complexity in mind, in this review we aim to provide an overview of cases in which the categorization of “coding gene” vs “non-coding gene” is outdated, since the same gene produces coding and non-coding elements.99 We also discuss the implications of this parsimonious usage of genetic units, in terms of independent or interdependent regulation of expression and concordant or discordant biological output in cancer. In addition, we point out the methodological advancements that are required to study bifunctional genes, with particular emphasis on the importance of in vivo modeling. Finally, we highlight the opportunities and challenges associated with the therapeutic implications of bifunctional genes in the development of anticancer therapies.

Bifunctional genomic loci express mRNAs and ncRNAs

There are genomic loci that can be rightfully considered both coding and non-coding because they express both an mRNA and a ncRNA, in a mutually exclusive or coexisting fashion (Fig. 1). Such genomic loci are defined “hybrid” or “bifunctional”, and representative cancer-relevant examples are described below.Fig. 1 Bifunctional genomic loci express mRNAs and ncRNAs.

Genomic loci are defined bifunctional when they can be considered both coding (orange) and non-coding (blue), because they express both an mRNA and a ncRNA, through one of the following mechanisms. a The ncRNA is the product of alternative splicing, for example through the retention of introns or the choice of an alternative splice site. b In back-splicing, the joining of an upstream 3′ splice acceptor with a 5′ downstream splice donor leads to the production of a non-coding circRNA. c NATs are non-coding RNA molecules transcribed from the opposite DNA strand. According to the degree of overlap with sense coding mRNAs, NATs are defined as head-to-head (the overlap is in the 5′ region, left), tail-to-tail (the overlap is in the 3′ region, middle) or embedded (the overlap is complete, right). d Exons compose the mRNA that is translated into a protein, while introns compose a non-coding RNA such as a miRNA. The ncRNA is called “intragenic”, while the coding gene in which it resides is called “host gene”.

Expression of an mRNA and a ncRNA depending on the exons spliced together

Alternative splicing (AS) is one of the mechanisms through which cells express more than one transcript from the same genomic locus, thereby enriching their transcriptome (and proteome). Alternative splicing comes in five main flavors (exon skipping, alternative 5′ splice site, alternative 3′ splice site, mutually exclusive exons, intron retention) and it can occur in conjunction with the use of alternative transcription start sites (promoters), or alternative polyadenylation sites.100–102

Several examples have been reported of genomic loci that undergo alternative splicing and end up expressing a coding transcript and a non-coding transcript with a role in cancer (Fig. 1a).103 Two of such examples are described below.

The Steroid Receptor RNA Activator 1 (SRA1) gene was the first bifunctional gene to be characterized. It expresses Steroid Receptor co-Activator Protein (SRAP), an oncogenic protein that acts as positive transcriptional regulator of steroid receptors. In breast cancer SRAP is overexpressed and associated with worse prognosis,104 while in prostate cancer it has been shown to potentiate the activity of the androgen receptor.105 Due to intron 1 retention,106 the SRA1 gene expresses lincRNA-SRA as well. Oncogenic lincRNA-SRA is overexpressed in melanoma. In this context, it induces cell proliferation, migration, invasion, epithelial to mesenchymal transition (EMT), as well as metastasis in a xenograft model.107 However, the molecular mechanism(s) of its action remain to be elucidated.

The PPP1R10 gene expresses Protein Phosphatase-1 (PP-1) Nuclear Targeting Subunit (PNUTS), a ubiquitous nuclear protein that binds to PP-1. In turn, PP-1 is a serine/threonine phosphatase mainly involved in chromosome decondensation at mitosis exit.108 PNUTS is a positive modulator of PP-1 activity, thereby favoring the re-entry into interphase.109 It is also involved in DNA damage repair.110 In the context of breast cancer, PPP1R10 gene expresses lncRNA-PNUTS as well, due to an alternative 3′ splice site that is located in exon 12 and breaks the ORF encoding PNUTS protein. lncRNA-PNUTS expression is under the regulation of TGF-β: through AKT2-dependent phosphorylation, TGF-β causes the release of hnRNP E1 splicing repressor from a TGF-β Activated Translational (BAT) element that is positioned at the alternative splice site. In this way, alternative splicing can occur and lncRNA-PNUTS is expressed. In turn, lncRNA-PNUTS acts as an effector of TGF-β-induced EMT, because it sponges ZEB1-targeting miR-205. lncRNA-PNUTS silencing is in fact associated with decreased tumor initiation and metastasis in a xenograft model.111

Among common mechanisms through which coding and non-coding transcripts are expressed from the same genomic locus, there is also back-splicing (Fig. 1b). There are several examples of genomic loci expressing a linear coding mRNA and a circular non-coding RNA with roles in cancer.84

Specifically, we have attributed an oncogenic role to circular Pokémon (circPOK) in the context of mesenchymal tumors. circPOK is an EcircRNA generated from the Zbtb7a gene through back-splicing of exon 2. It promotes tumorigenesis by binding to the complex formed by InterLeukin enhancer binding Factor 2 and 3 (ILF2/3), hence sustaining the transcription/stability of multiple mRNAs encoding interleukins and angiogenic factors.112 Interestingly, the linear transcript expressed from Zbtb7a gene encodes Zbtb7a/Pokémon/Lrf, a transcriptional repressor that acts as a tumor suppressor of mesenchymal tumorigenesis, by promoting the differentiation of mesenchymal stem cells.113 The discordant functions of the linear coding transcript vs the circular non-coding transcript are confirmed by the opposite trend observed in their expression levels when mesenchymal tumors are compared to normal tissues: Pokémon levels are lower, while circPOK levels are higher. The decrease in Pokémon levels is due to enhanced post-transcriptional regulation by oncogenic miRNAs,112 while the mechanism behind the increase in circPOK remains to be established.

Expression of a sense mRNA and an antisense ncRNA

In cancer, there are quite a few examples of genomic loci that are transcribed from both DNA strands and end up expressing a sense coding mRNA and an antisense non-coding RNA, i.e., an NAT (Fig. 1c).65,66 Two of such examples are described below.

As an example of cis-NAT, we highlight the oncogenic ZEB1-AS1. Zinc finger E-box-Binding homeobox 1 (ZEB1) is an oncogenic transcription factor overexpressed in many epithelial tumor types. ZEB1 is a master regulator of EMT, promoting migration/invasion in vitro and metastasis in vivo. It also confers resistance to chemotherapy.114 ZEB-AS1 is transcribed in antisense orientation from the promoter region of ZEB1 and in turn is involved in a positive feedback loop, sustaining ZEB1 expression at two levels. It promotes ZEB1 transcription epigenetically. This is because it can recruit Mixed Lineage Leukemia 1 (MLL1) histone methyltransferase on the ZEB1 promoter, therefore ensuring that H3 histone gets methylated at K4 (H3K4me3) and that DNA is accessible for transcription.115 In addition, ZEB-AS1 sponges several anti-EMT miRNAs, including miR-200 family and miR-205, that in turn target ZEB1.116,117

As an example of trans-NAT, we mention the tumor-suppressive CDR1as. Cerebellum Degeneration-Related antigen 1 (CDR1) is a low-expressed, poorly-characterized one-exon gene. LINC00632 is a 5-exon lincRNA transcribed in antisense orientation compared to CDR1. CDR1as is generated by back-splicing of the 5th exon of LINC00632, which fully overlaps with CDR1.118 CDR1as is highly expressed in the brain, where it belongs to a sophisticated network that tightly regulates miR-7 level/activity and is involved in correct embryonic development.119–124 Conversely, CDR1as is expressed at low levels in all other tissues, except for melanocytes that share neural crest origin with the brain.125 In cancer, CDR1as is reported as downregulated both in gliomas and in melanoma, and it has been implicated in the regulation of protein stability and function.126 In gliomas, it stabilizes p53 by binding to it, hence preventing the binding of MDM2 and the consequent proteasome-dependent degradation.127 In melanoma, CDR1as inactivates the pro-metastatic IGF2BP3 protein by sponging it.128

Expression of an mRNA from exons and of a ncRNA from introns of the same pre-mRNA

Bifunctional genomic loci exist where exons compose the mRNA that is translated into a protein, while introns compose a ncRNA. Such ncRNAs are called “intragenic” and the coding genes in which they reside are referred to as “host genes”.129

This arrangement is very common with miRNAs (Fig. 1d). Hundreds of miRNA genes are in fact located within introns of protein-coding genes. They can be transcribed from their own promoters as independent transcriptional units, but more commonly transcription starts from the promoter of the host gene and produces a bifunctional pre-mRNA: exons are spliced together into the mRNA, while the intronic pri-miRNA is further processed into mature miRNA(s). Consequently, miRNA(s) and host gene are co-expressed and co-involved in regulatory circuits.130–132

miR-106~25 cluster of miRNAs is composed of miR-106b, miR-93 and miR-25. It is located in the 13th intron of Mini-Chromosome Maintenance protein 7 (MCM7) gene and is produced through pre-mRNA splicing. Both the miRNA cluster and the protein are aberrantly overexpressed in prostate cancer. MCM7 protein promotes the initiation of genome replication, while miR-106b~25 is responsible for the decrease of PTEN levels by binding to 3′UTR of PTEN. By generating a vector that drives the expression of MCM7 exons as well as intron 13 (PIG/MCM7i13), we demonstrated that MCM7 protein and the miR-106~25 cluster can transform mouse embryonic fibroblasts in vitro. We then moved into the in vivo setting.Fig. 2 Bifunctional mRNAs exert coding functions and non-coding functions.

In mRNA molecules (middle) three regions can be identified: the 5′UTR (red), the CDS (light blue) and the 3′UTR (green). (Top, orange) mRNAs are primarily protein-coding RNA molecules: they carry a primary ORF (the CDS), and they may also present a short uORF in the 5′UTR. (Bottom, blue) non-canonical non-coding functions have been attributed to mRNAs. The 5′UTR can exert non-coding functions in cis or in trans, by interacting with proteins. The CDS can be involved in non-coding RNA–protein or RNA–RNA interactions. The 3′UTR can exert non-coding functions within the concept of ceRNAs: due to MREs, 3′UTRs can sponge miRNAs, leading to the de-silencing of ceRNA partners that share MREs for the same miRNAs.

The MCM7i13 construct was placed under the control of the prostate-specific rat Probasin promoter ARR2PB (Pb/MCM7i13). Nine transgenic lines were analyzed and clustered into low expressor (LE), medium expressor (ME) and high expressor (HE), according to the degree of overexpression of MCM7, miR-106b, miR-93 and miR-25. By analyzing a cohort of 1-year-old transgenic mice belonging to the various lines, we observed that the dorsolateral prostates (DLPs) displayed multifocal lesions whose severity correlated with transgene expression levels: while LE mice showed just hyperplasia, ME and even more HE mice showed typical histological features of prostatic intraepithelial neoplasia (PIN). In the DLPs of HE transgenic mice aberrant proliferation was confirmed by increased number of Ki67-positive cells, while the downregulation of Pten mRNA levels together with hyperactivation of Akt signaling was consistent with the activity of miR-106~25 as a Pten-targeting cluster. These data confirm that the MCM7 protein and the miR-106~25 cluster are 2 hits that can initiate prostate tumorigenesis in a tissue-specific mouse model. Interestingly, Pb/MCM7 transgenic mice were generated as well. However, no signs of PIN were visible up to 1 year of age. This further confirms that MCM7 protein cannot initiate prostate tumorigenesis alone and that miR-106~25 non-coding cluster is indispensable.133

In conclusion, all these specific examples concur to highlight the complexity of gene expression and demonstrate that a single genomic locus can exert both coding functions, through the transcription of an mRNA and the synthesis of the corresponding protein, and non-coding functions, by expressing a ncRNA, with important biological outcomes.

Bifunctional mRNAs exert non-coding functions as well

mRNAs are protein-coding RNAs, as their fate is to be exported from the nucleus to the cytoplasm, where they are translated into proteins. However, literature provides extensive evidence that mRNAs exert non-coding functions as well.

Here, we present examples of “bifunctional mRNAs” and of the role that they play in cancer because of the non-coding activities of their 5′UTR, CDS and 3′UTR (Fig. 2).

The 5′UTR exerts non-coding functions

Two clear examples of 5′UTRs with non-coding functions are represented by the c-Myc and Vascular Endothelial Growth Factor (VEGF) genes. One (c-MYC P0 5′UTR) behaves as a tumor suppressor and the other (VEGF 5′UTR) as an oncogene.

The proto-oncogene c-MYC promotes cell proliferation and tumorigenesis. Although the most expressed c-MYC mRNAs are transcribed from the P1 and P2 transcription start sites, 5% of c-MYC transcripts are expressed from the upstream P0 transcription start site. P0 transcript is under the control of its own promoter and differs from the predominant P1 and P2 transcripts because of an extended 5′UTR (~640-nt extension). Blume et al.134 discovered that the overexpression of P0 5′UTR strongly decreases the anchorage-independent growth of HeLa cells in vitro, and their ability to form tumors when xenografted in nude mice. Digging into the molecular mechanism underlying this phenomenon, they found that P0 5′UTR overexpression is associated with the upregulation of the c-MYC2 (p64) protein, which is translated from the P2 transcript. Such upregulation results in increased apoptotic cell death, likely a failsafe mechanism triggered in the presence of excessive oncogenic signaling.135 Since no increase was observed in the level of the endogenous P2 transcript, the authors hypothesized that P0 5′UTR might work in cis by affecting the translation of the abovementioned c-MYC2 protein isoform, either directly through P0–P2 RNA interactions or indirectly through RBPs. It also remains to be elucidated which transcription factors control transcription from P0 vs P1/2 start site and how the choice is regulated in physiological and pathological conditions.

VEGF plays a critical role in tumorigenesis through promotion of neoangiogenesis.136 However, the susceptibility of HCT116 colon cancer cells to chemotherapeutic agents (5-fluorouracil, etoposide and doxorubicin) is not fully rescued by recombinant VEGF protein, which raises the possibility that VEGF mRNA exerts coding-independent functions. Masuda et al.137 unveiled that the overexpression of VEGF 5′UTR increases the anchorage-independent growth of HCT116 cells in vitro, and their ability to form tumors when xenografted in athymic nude mice. These tumors were profiled by microarray analysis, showing the upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes. Specifically, the authors observed a decrease in IFNα/STAT1-dependent pro-apoptotic signaling pathway, which resulted in decreased sensitivity of xenografted tumors to 5-fluorouracil, a chemotherapeutic agent that is known to elicit an IFNα/STAT1-dependent pro-apoptotic response. The tumor-promoting function was mapped to a 270 nt-long region located between 475 nt and 745 nt of VEGF 5′UTR and persisted when cells were treated with the translation inhibitor cycloheximide, which proves that it is not related to protein synthesis. However, the exact molecular mechanism still needs to be elucidated. Considering the wide impact on transcriptome and the strong biological effects, the authors speculate that VEGF 5′UTR works in trans as a regulatory RNA that affects the expression/functions of a wide network of target proteins.137

The CDS exerts non-coding functions

The CDS is the region of the mRNA whose fate is to be translated, as its nucleotide sequence instructs the amino acid sequence of the protein, and that is why mRNAs are transcripts that primarily exert a coding function. However, there are cancer-relevant examples by which the CDS exerts a non-coding function as well.

The p53 transcription factor is a tumor suppressor protein that prevents cancerous transformation, mainly acting as a keeper of genome integrity.138 Under normal conditions p53 is kept inactive, while under stress conditions it gets rapidly activated. This is possible due to the tight control exerted by the MDM2 protein on p53. MDM2 binds to p53 and, functioning as an E3 ligase, triggers the ubiquitination of p53 C-terminal domain, and consequent proteasome-mediated degradation in the cytoplasm. Under stress conditions, MDM2 quickly releases its hold, so that p53 level increases, gets localized to the nucleus, and unleashes its activity as a transcription factor. Consequently, cells stop cycling and either repair the damage or die by apoptosis. Once damage is repaired, multiple negative feedback loops place p53 back under MDM2 control, so that the permanent blockage of cell functions is avoided.139

Extensive literature has unveiled the mechanisms through which p53 level increases in response to stress. DNA damage induces multiple post-translational modifications of p53 protein (phosphorylation and acetylation) that weaken its interaction with MDM2. It also induces p14/ARF that inactivates MDM2 by sequestering it into the nucleolus. Finally, relevant to the main topic of this review, the DNA damage sensor ATM phosphorylates MDM2 at Ser395. This induces a conformational change in the protein and favors its interaction with a specific sequence within the CDS of p53 mRNA. Because of this interaction, MDM2 switches from a negative to a positive regulator of p53: it cannot function as E3 ligase any longer, and it rather promotes p53 mRNA translation, contributing to the increased levels of p53 protein.140–142 Noteworthily, the BOX-I domain, which is the domain used by p53 protein to interact with MDM2 protein, is translated from the sequence used by p53 mRNA to interact with MDM2 protein. Furthermore, the BOX-I domain is the most conserved region of p53 protein and has co-evolved with MDM2 protein. This attests that the coding and the non-coding functions of p53 mRNA are equally important to ensure the fine regulation of p53 activation/deactivation.143

In normal somatic cells, progressive telomere shortening along with cell divisions results in replicative senescence. Conversely, cancer cells aberrantly express the TElomerase Reverse Transcriptase (TERT) enzyme that forms a ribonucleoprotein (RNP) with Telomerase RNA (TR) and uses it as a template to extend telomere length, counteracting telomere erosion. Since TR level exceeds TERT level, TERT-independent functions have been postulated for TR. Ivanyi-Nagy et al.144 used a pull-down approach to map the RNA interactome of TR. Among the candidates further studied, HIST1H1C, the mRNA of H1.2 linker histone subtype, was found to exert a non-coding activity through its CDS. Within HIST1H1C CDS, nucleotides 334–348 form an RNA duplex with TR and were named Telomerase RNA InterActing Genetic Element (TRIAGE). The direct interaction of TRIAGE with TR does not affect TERT enzymatic activity, and yet it has a negative impact on telomere elongation. The authors hypothesize that, by base pairing with TR, TRIAGE sponges TERT RNP away from telomeres, impairing their elongation.

The 3′UTR exerts non-coding functions

It is well established that 3′UTRs exert regulatory functions and have an impact on tumorigenesis. For example, we have recently reported in a zebrafish model of melanoma that the presence of the 3′UTR impacts on BRAFV600E-driven tumorigenesis. The strong melanoma driver effect of the CDS of reference BRAFV600E (BRAFV600E-ref) is in fact suppressed in the presence of the corresponding 3′UTR.145

3′UTRs are post-transcriptional regulators of gene expression, and they exert both in cis and in trans functions. In cis functions are mainly coding-related, as they involve the regulation of stability, localization, and translation of the mRNA itself.146,147 By contrast, the mechanism through which 3′UTRs exert their non-coding function in trans falls within the concept of mRNAs as sponges for miRNAs, i.e., as ceRNAs. Hundreds of papers about this topic have been published in the last decade, most of which are in the context of cancer. Indeed, when 3′UTR-dependent functions are at play, the overexpression of an oncogenic mRNA or the downregulation of a tumor-suppressive mRNA promotes cancer initiation and/or progression not only because of the encoded protein, but also because of the ceRNA activity of its 3′UTR. Three examples are described below.

In breast cancer the CXCR4 mRNA promotes metastasis not only through its protein, the CXCR4 chemokine receptor, but also through the CXCR4 3′UTR that sponges the tumor-suppressive miR-146a, thus leading to the upregulation of TRAF6 and EGFR, two oncoproteins that activate the NF-κB pathway.148

The PTEN mRNA is renowned to suppress oncogenic PI3K/AKT signaling pathway through the PTEN protein, a phosphatase that dephosphorylates phosphatidylinositol-3,4,5-trisphosphate (PIP3) to phosphatidylinositol-4,5-biphosphate (PIP2) and in so doing prevents downstream AKT activation.149 However, the PTEN mRNA exerts a tumor-suppressive function also by sponging oncogenic miRNAs, and hence by sustaining the expression of tumor-suppressive ceRNA partners involved in other signaling pathways.70,150,151 In turn, the ceRNA network of mRNAs that sustains the expression of the PTEN mRNA, and hence the inhibition of the PI3K/AKT signaling pathway, is even more extended34,150–155 and fatally gets heavily affected by the widespread 3′UTR shortening that occurs in cancer.156

Quite interesting is also the case of the ZEB1 and ZEB2 transcription factors and master regulators of EMT (see “Expression of a sense mRNA and an antisense ncRNA” chapter above). In epithelial tumors, the ZEB1 protein is oncogenic because it promotes EMT not only directly (by repressing the transcription of miR-200 family), but also indirectly: it induced the transcription of Integrin A1 mRNA, which in turn sponges the tumor-suppressive miR-181b away from Adenylyl Cyclase 9 (ADCY9) mRNA. As a result, the levels of ADCY9 protein increase, as well as those of cyclic AMP, which favors metastatic dissemination.157 In melanoma ZEB2 behaves as a tumor suppressor not only because ZEB2 protein activates MITF-dependent differentiation program,158 but also because ZEB2 3′UTR has PTEN mRNA as ceRNA partner.151

For further examples of specific mRNAs with ceRNA activity, please refer to Table 1. Examples of extended ceRNA networks that revolve around mRNAs are reported in.153,159–161Table 1 List of mRNAs that exert ceRNA activity in human cancer due to their 3'UTR.

3'UTR	miRNA	DE-SILENCED mRNA	TUMOR TYPE	SPONGING ACTIVITY OUTPUT	IN VIVO MODELS	Ref #	
			Non Small Cell Lung Cancer	Oncogenic	-	214	
			Colorectal Cancer	Tumor-suppressive	xenograft	215	
			Breast Cancer	Tumor-suppressive	xenograft	216	
			Breast Cancer	Oncogenic	xenograft	217	
			Breast Cancer	Oncogenic	xenograft	217	
			Breast Cancer	Tumor-suppressive	xenograft	218	
			Liver Cancer Stem Cells	Tumor-suppressive	-	219	
			Breast Cancer	Tumor-suppressive	xenograft + patients	220	
			Urothelial Carcinoma	Oncogenic	xenograft + patients	221	
			Colorectal Cancer and Prostate Cancer	Tumor-suppressive	ref. 151	150	
			Breast Cancer	Oncogenic	-	148	
			Breast Cancer	Tumor-suppressive	-	222	
			Breast Cancer	Oncogenic	chick embryo + rat	223,224	
			Colorectal Cancer	Tumor-suppressive	-	155	
			Ovarian Cancer	Oncogenic	xenograft + patients	225	
			Breast Cancer	Tumor-suppressive	-	226	
			Lung Cancer (+713P, 307P, 344LN, 393LN, 393P, 412P, 344SQ, 344P, 531LN1, 531LN2, 531P1, and 531P2 murine cell lines)	Oncogenic	xenograft	157	
			Hepatocellular Carcinoma	Oncogenic	xenograft + patients	227	
			Oral Squamous Cell Carcinoma	Oncogenic	patients	228	
			Non Small Cell Lung Cancer	Oncogenic	patients	229	
			Triple Negative Breast Cancer (+4T1 murine cell line)	Oncogenic	xenograft + patients	230	
			Hepatocellular Carcinoma	Oncogenic	xenograft + patients	231	
			Non Small Cell Lung Cancer	Oncogenic	-	232	
			Ovarian Cancer	Oncogenic	-	233	
			Ovarian Cancer	Oncogenic	-	234	
			Breast Cancer	Tumor-suppressive	-	235	
			Breast Cancer	Tumor-suppressive	xenograft	236	
			Breast Cancer	Tumor-suppressive	xenograft	237	
			Hepatocellular Carcinoma	Tumor-suppressive	patients	238	
			Prostate Cancer	Tumor-suppressive	-	154	
			Colorectal Cancer	Tumor-suppressive	xenograft + patients	239	
			Colorectal Cancer and Prostate Cancer	Tumor-suppressive	-	150	
			Hepatocellular Carcinoma	Oncogenic	transgenic mice + patients	240	
			Breast Cancer (+4T1 murine cell line)	Tumor-suppressive	xenograft + transgenic mice	152	
			Breast Cancer (+4T1 murine cell line)	Tumor-suppressive	xenograft + transgenic mice	152	
			Breast Cancer and Colorectal Cancer	Oncogenic	xenograft	241	
			Hepatocellular Carcinoma	Oncogenic	-	242	
			Colorectal Cancer and Melanoma (+TB13602 murine cell line)	Tumor-suppressive	xenograft + transgenic mice	151	

Bold: examples described in the text

Bifunctional ncRNAs exert coding functions as well

In the last years, polysome/ribosome profiling and mass spectroscopy analyses have provided evidence that, together with162 or alternatively to163–165 coding-independent activities, ncRNAs can carry ORFs that are translated into ncRNA-encoded peptides (ncPEPs).166–168 The ~100 ncPEPs characterized so far are mostly short (< 100 aa), but longer examples exist.167,169–171 Many of these ncPEPs have an impact in cancer, as described below (Fig. 3).Fig. 3 Bifunctional ncRNAs exert non-coding functions and coding functions.

ncRNAs can be divided into two groups: housekeeping ncRNAs (upper panels) and regulatory ncRNAs (lower panels). Among housekeeping ncRNAs there are rRNAs, tRNAs, snRNAs and snoRNAs. Regulatory ncRNAs are further divided according to their length. Among short ncRNAs (< 200 nt) there are miRNAs (light blue). Long ncRNAs (lncRNAs, ≥ 500 nt) include lincRNAs (light green), pseudogenic RNAs (PGs, light gray), NATs (see Fig. 1c), and circRNAs (light purple). The primary function of miRNAs is non-coding (blue) and relates to post-transcriptional regulation of gene expression: mRNA degradation or translational repression mediated by the RISC complex. Among non-coding functions of lincRNAs there are: chromatin remodeling by epigenetic modification, transcription and splicing regulation, sponging of miRNAs and proteins, post-translational modification of proteins. Non-coding functions of PGs can be parental gene (PA)-related or unrelated. They include sponging of miRNAs and proteins, and mRNA degradation through endosiRNAs. S sense strand, AS antisense strand. circRNAs can be composed by only exons (EcircRNAs), both exons and introns (EIcircRNAs), or only introns (ciRNAs). They exert non-coding functions by acting as sponges for miRNAs and proteins, and by forming circRNPs that modulate signaling pathways. These groups of regulatory ncRNAs can all exert non-canonical coding functions as well, because they can be translated into ncPEPs, i.e., small peptides or proteins (orange).

Translation of pri-miRNAs

The presence of a short ORF has been demonstrated within the pri-miRNA of miR-200a and miR-200b, two miRNAs with tumor-suppressive activity that inhibit metastasis by blocking EMT (see “Expression of a sense mRNA and an antisense ncRNA” chapter and “The 3′UTR exerts non-coding functions” chapter above). When overexpressed in prostate cancer cells, these pri-miRNA-encoded peptides, called miPEP-200a and miPEP-200b, have been shown to inhibit migration and to impair EMT. However, the molecular mechanism of action and the potential synergy with the corresponding miRNAs remain to be established.172

Translation of lincRNAs

Recent reports indicate that several lincRNAs contain ORFs that encode peptides and attest the importance of this feature in the development and progression of cancer.59 Two examples are described below.

LINC00665 is a lincRNA aberrantly expressed in more than 15 cancer types. It is involved in several signaling pathways (Wnt/β-Catenin, TGF-β, NF-κB, PI3K/AKT, and MAPK) and has attracted attention as a diagnostic and prognostic marker. In most of the cases, LINC00665 is an oncogenic lincRNA that exerts non-coding activities by working as ceRNA for more than 20 miRNAs, as well as by binding to chromatin remodeling factors and transcriptional regulators.163 By contrast, in triple-negative breast cancer (TNBC), it acts as a tumor-suppressive lincRNA that expresses CIP2A-BP. This is a 52-aa peptide that in vitro inhibits migration and invasion of TNBC cells. Mechanistically, CIP2A-BP impairs the PI3K/AKT signaling pathway by binding to Cellular Inhibitor of PP2A (CIP2A). Consequently, CIP2A no longer binds to PP2A phosphatase, and in turn PP2A inactivates AKT by dephosphorylation at Thr308 and Ser473 residues. Conversely, the EMT-promoting TGF-β signaling pathway actively downregulates CIP2A-BP. Specifically, the TGF-β effector SMAD4 upregulates 4E-BP1 transcription. In turn, 4E-BP1 binds to eIF4F and inhibits translation of many proteins, including CIP2A-BP.173

To study the role of the CIP2A-BP peptide in tumorigenesis in vivo, a knock-in (KI) mouse model was developed. Specifically, homologous recombination was used to knock in CIP2A-BP ORF, preceded by a loxed STOP codon, into the ROSA26 (R26) locus, which ensures robust transcription under the R26 promoter. KI mice were then crossed with CMV-Cre mice so that homozygous CIP2A-BP+/+ mice were obtained, which show constitutive and ubiquitous CIP2A-BP translation. Finally, CIP2A-BP+/+ mice were further crossed with breast cancer-prone MMTV-PyMT mice, obtaining MMTV-PyMT;CIP2A-BP+/+ mice. MMTV-PyMT is the most widely used genetically engineered model (GEM) of breast cancer in the mouse. In this model, Murine Mammary Tumor Virus (MMTV) Long Terminal Repeat (LTR) promoter restricts the expression of PolYoma Middle T antigen (PyMT) to the mammary epithelium. This leads to the formation of multifocal primary tumors that have high tendency to metastasize to the lung.174 In accordance with in vitro data, the combined expression of PyMT and CIP2A-BP in the mammary epithelium, which characterizes MMTV-PyMT;CIP2A-BP+/+ mice, is associated with decreased AKT phosphorylation in primary tumors and decreased number of metastatic nodules in the lungs.173

Another interesting example is represented by LINC00998. In hepatocellular carcinoma (HCC), LINC00998 is upregulated and is associated with worse prognosis. This lincRNA is under the transcriptional control by c-MYC and expresses a 59-aa peptide termed SMIM30, which shows oncogenic properties both in vitro and in xenograft mouse models. In fact, SMIM30 overexpression results in increased proliferation, migration and invasion. Mechanistically, SMIM30 localizes at the plasma membrane, where it binds to YES1, a member of SRC tyrosine kinase family. Binding to SMIM30 increases membrane anchoring of YES1 and facilitates downstream activation of oncogenic MAPK signaling pathway.175

Additional examples of lincRNA-encoded peptides are listed in Table 2 (upper).Table 2 List of lincRNAs and PGs that are translated into peptides/proteins with a role in human cancer.

lincRNA	ENCODED PEPTIDE	TUMOR TYPE	PEPTIDE EXPRESSION LEVEL	PEPTIDE ACTIVITY OUTPUT	PEPTIDE BIOLOGICAL ACTIVITY	IN VIVO MODELS	Ref #	
LINC00266-1	RBRP	Colorectal cancer		Oncogenic	Binding to the m6A reader IGF2BP1. This results in increased c-Myc expression.	xenograft + patients	243	
LINC00278	YY1BM	Esophageal squamous cell carcinoma		Tumor-suppressive	Separation of YY1 from AR. This results in eEF2k downregulation.	xenograft + patients	244	
LINC00665	CIP2A-BP	Triple negative breast cancer		Tumor-suppressive	Binding to CIP2A. This results in increased dephosphorylation of AKT by PP2A, hence decreased signaling through the PI3K/AKT pathway.	xenograft + transgenic mice + patients	173	
LINC00675	FORCP	Colorectal cancer		Tumor-suppressive	Promotion of cancer cell apoptosis and suppression of tumorigenesis, possibly through the regulation of BRI3BP function.	xenograft	245	
LINC00908	ASRPS	Triple negative breast cancer		Tumor-suppressive	Impairment of STAT3 phosphorylation. This results in decreased VEGF expression.	xenograft + transgenic mice + patients	246	
LINC00998	SMIM30	Hepatocellular carcinoma		Oncogenic	Binding to YES1. This results in increased signaling through the MAPK pathway.	xenograft + patients	175	
PG	ENCODED PEPTIDE	TUMOR TYPE	PEPTIDE EXPRESSION LEVEL	PEPTIDE ACTIVITY OUTPUT	PEPTIDE BIOLOGICAL ACTIVITY	IN VIVO MODELS		
BRAF pseudogene	BRAF pseudogene peptide	Thyroid cancer (+CHO hamster cell line and NIH3T3 murine cell line)		Oncogenic	Promotion of signaling through the MAPK pathway. This leads to NIH3T3 cell transformation.	xenograft + patients	247	
CRIPTO3	CRIPTO3 protein	Cancer (+F9 murine cells (cripto–/–, Nodal+))		Oncogenic	Activation of Nodal signaling pathway.	patients	248	
MAPK6P4	P4-135aa	Glioblastoma		Oncogenic	Phosphorylation and stabilization of KLF15.	xenograft + patients	249	
NANOGP8	NANOGP8 protein	Prostate cancer		Oncogenic	Cancer initiation in combination with c-MYC.	transgenic mice	192	
NA88-A	NA88-A peptide	Melanoma		Tumor-suppressive	Antigenic peptide that is recognized by CD8+ T cells.	–	250	
OCT4-PG1	OCT4-PG1 protein	Chronic myeloid leukemia		Oncogenic	Alteration of multidrug resistance phenotype by directly interacting with OCT4, SOX2, and NANOG and indirectly with ABC transporters.	–	251	
STK24P1	P1-121aa	Glioblastoma		Oncogenic	Phosphorylation and stabilization of ELF2. This results in increased VEGFR2 and VE-cadherin expression.	xenograft + patients	252	
Bold: examples described in the text

Translation of PGs

It was estimated that dozens of pseudogenic proteins exist, and some can be longer than 100 aa.176 They are mostly expressed from processed pseudogenes, therefore they do not share the same promoter with their parental genes and, although they might be highly homologous in sequence, they get expressed in distinct tissues, subcellular compartments, or pathophysiological conditions. Pseudogenic proteins specifically expressed in cancer might also carry mutations that further alter their functioning.68,177

NANOGP8 is an example of pseudogenic protein with an oncogenic role. Together with LIN28, OCT4 and SOX2, NANOG forms a core network of transcription factors that regulate self-renewal of stem cells. Cancer cells often re-acquire stem-like properties and one of the mechanisms is the aberrant expression of NANOGP8, the NANOG-like protein translated from NANOGP8 processed pseudogene.178,179 NANOGP8 is detectable in various cancer types, including prostate cancer and cancers of the gastrointestinal tract, and its levels are particularly high in the cancer stem cell subpopulation.180–185 Accordingly, NANOGP8 displays oncogenic properties: it promotes clonogenicity, survival, proliferation, migration, anchorage-independent growth and resistance to anticancer drugs, both in vitro and in xenograft models.186–190 Furthermore, a NANOGP8 signature is associated with worse prognosis.191

Importantly, a transgenic mouse model was developed to study the contribution of NANPOGP8 to prostate tumorigenesis in vivo. The ORF of NANOGP8 was placed under the control of the prostate-specific Probasin promoter mentioned above (Pb/NANOGP8). After monitoring a cohort of transgenic animals for up to 2 years, the authors did not observe histological evidence of hyperplasia or PIN. However, when they crossed Pb/NANOGP8 transgenic mice with Pb/c-MYC transgenic mice, they observed an exacerbated phenotype, with thicker epithelial layers containing more atypical cells. These results indicate that NANOGP8 is not sufficient to initiate prostate cancer, although it cooperates with c-MYC.192 Interestingly, similar results were obtained in additional transgenic models. When NANOGP8 was overexpressed in epithelial organs through the Cytokeratin 14 (K14) promoter, no spontaneous tumor development was detected even after a prolonged time of observation.193 Analogously, the targeted overexpression of Nanog in the mammary gland was not sufficient to induce mammary tumors. However, in the presence of the concomitant overexpression of Wnt-1, Nanog contributed to the decreased mouse survival due to highly enhanced metastatic burden.194 In summary, NANOGP8 overexpression/inhibition causes a strong increase/decrease in prostate cancer cell line growth, when xenografted into immunodeficient mice,180–182,186,191,195 but NANOGP8 overexpression is unable to initiate prostate tumorigenesis in a transgenic mouse.192,193 These results show the importance of GEMs to assess the specific role played by the gene of interest in each phase of cancer development, from initiation to metastasis.

Additional examples of PG-encoded peptides are listed in Table 2 (lower).

Translation of circRNAs

About 1% of circRNAs are translated.81 This mainly applies to circRNAs composed only by exons (EcircRNAs), as they localize in the cytoplasm.196 Translation remains polysome-dependent, but, in the absence of 5′ cap and 3′ polyA tail, it is cap-independent. Three main mechanisms have been identified thus far. One relies on the presence of an Internal Ribosome Entry Site (IRES), a sequence that can directly recruit ribosomes to initiate translation. Another cap-independent translation mechanism is mediated by N6-methyladenosine (m6A) residues. It has been reported that at least 13% of circRNAs carry m6A modifications and that just one modification per circRNA is sufficient to promote the recruitment of the m6A reader YTHDF3, as well as eIF3A and eIF4s (A, B, G2) translation initiation factors. Finally, rolling translation occurs when the circRNA harbors the ATG, but not the stop codon. Translation is carried on in an infinite circle, until it is interrupted through a mechanism termed –1 Programmed Ribosomal Frameshifting (–1 PRF)-mediated Out-of-frame Stop Codon (OSC).197–199

circRNA translation is a field that has just started to be explored. Approaches for the detection of circRNA-encoded peptides200 and tools for their study201 have been developed. Yet, they require further refinement to exclude the unintended detection of peptides produced by the linear counterparts.200 Nevertheless, solid experimental evidence is accumulating about circRNA-encoded peptides that play key roles in cancer.202–204 Two examples are described below.

In glioblastoma multiforme (GBM), AKT3-174aa ncPEP is encoded by hsa_circ_0017250/circAKT3, a circRNA that comprises exons 3–7 of the AKT3 gene. Together with AKT1 and 2, AKT3 is an oncogenic kinase with a well-established role in the PI3K/AKT signaling pathway. Since they activate key downstream effectors of this pathway, AKTs are involved in many aspects of tumor initiation and progression, up to metastasis and drug resistance. They are also actively investigated as therapeutic targets.205 AKT3-174aa shows decreased expression levels in GBM tissues compared to adjacent normal brain tissues and displays oncosuppressive properties: when overexpressed, it decreases GBM cell proliferation in vitro and in xenograft models. It also increases sensitivity to radiation. Furthermore, higher AKT3-174aa levels are associated with better prognosis in patients. Mechanistically, AKT3-174aa competes with AKT3 for binding to phosphoinositide-dependent kinase-1 (PDK1). In so doing, it prevents AKT3 activation by phosphorylation on Thr308. Therefore, AKT3-174aa should be considered as a dominant-negative AKT3 isoform that restrains AKT3 activity through a negative feedback loop.164

In GBM and TNBC, FBXW7-185aa ncPEP is encoded by hsa_circ_022705/circFBXW7, a circRNA that comprises exons 3–4 of the FBXW7 gene. FBXW7 is a tumor-suppressive E3 ubiquitin ligase that targets multiple oncogenic proteins, including c-MYC, for proteasome-dependent degradation.206 FBXW7-185aa shows decreased expression levels in cancer tissues compared to adjacent normal tissues and has tumor-suppressive properties: when overexpressed, it decreases cancer cell proliferation in vitro and in xenograft models. Furthermore, higher FBXW7-185aa levels are associated with better prognosis in patients. Mechanistically, FBXW7-185aa has a strong affinity for Ubiquitin Specific Protease 28 (USP28), a de-ubiquitinating enzyme that prevents c-MYC degradation. By binding to USP28, FBXW7-185aa impairs its binding to c-MYC, and hence enhances the proteasome-dependent degradation induced by FBXW7.162,207 Interestingly, in TNBC hsa_circ_022705 not only favors FBXW7 activity through FBXW7-185aa ncPEP, but also sustains FBXW7 expression by sponging miR-197-3p.162

Additional examples of circRNA-encoded peptides are listed in Table 3.Table 3 List of circRNAs that are translated into peptides with a role in human cancer.

circRNA	ENCODED PEPTIDE	TUMOR TYPE	PEPTIDE EXPRESSION LEVEL	PEPTIDE ACTIVITY OUTPUT	PEPTIDE BIOLOGICAL ACTIVITY	IN VIVO MODELS	Ref #	
circAKT3	AKT3-174aa	Glioblastoma		Tumor-suppressive	Competitive binding to PDK1. This results in decreased AKT3 phosphorylation, hence decreased signaling through the PI3K/AKT pathway.	xenograft + patients	164	
circASK1	ASK1‐272aa	Lung adenocarcinoma		Tumor-suppressive	Competitive binding to AKT1. In this way ASK1 is released from phosphorylation‐mediated inactivation.	patients	253	
circAXIN1	AXIN1‐295aa	Gastric cancer		Oncogenic	Binding to APC. This prevents the interaction of APC with AXIN1, abolishing its inhibitory effect. As a result, signaling through the Wnt/β‐Catenin pathway increases.	xenograft + patients	254	
circβ‐Catenin	β-Catenin-370aa	Non-small cell lung cancer		Oncogenic	Competitive binding to GSK3β, which prevents the GSK3β‐mediated degradation of β‐Catenin. This results in increased signaling through the Wnt/β‐Catenin pathway.	patients	255	
		Liver cancer		Oncogenic		xenograft + patients	256	
circCHEK	circCHEK1-246aa	Multiple myeloma		Oncogenic	Promotion of cell proliferation through chromosomal instability; enhancement of macrophage‐osteoclast differentiation.	xenograft	257	
circDIDO1	DIDO1‐529aa	Gastric cancer		Tumor-suppressive	Promotion of the ubiquitin‐mediated degradation of PRDX2.	xenograft + patients	258	
circE‐Cad	C‐E‐Cad	Glioblastoma		Oncogenic	Promotion of EGFR signaling.	xenograft + patients	259	
circEIF6	EIF6‐224aa	Triple negative breast cancer		Oncogenic	Promotion of the MYH9/Wnt/β‐Catenin signaling pathway.	xenograft + patients	260	
circFBXW7	FBXW7-185aa	Glioma		Tumor-suppressive	Binding to USP28. This favors the proteasome-dependent degradation of c‐Myc induced by FBXW7.	xenograft + patients	207	
		Triple negative breast cancer				xenograft + patients	162	
circFGFR1	circFGFR1p	Cancer		Tumor-suppressive	Negative regulation of FGFR1.	–	261	
circFNDC3B	circFNDC3B‐218aa	Colorectal cancer		Tumor-suppressive	Inhibition of the Snail‐FBP‐EMT axis.	xenograft + patients	262	
circGprc5a	circGprc5a-peptide	Bladder cancer		Oncogenic	Binding to Gprc5A. This results in increased signaling through the GPCR pathway.	patients	263	
circHEATR5B	HEATR5B‐881aa	Glioblastoma		Tumor-suppressive	Mediation of the inhibitory effect of circHEATR5B.	xenograft + patients	264	
circ‐HER2	HER2‐103	Triple negative breast cancer		Oncogenic	Binding to EGFR and HER3. This results in increased EGFR signaling.	xenograft + patients	265	
circMAPK1	MAPK1‐109aa	Gastric cancer		Tumor-suppressive	Inhibition of MAPK1 phosphorylation. This results in decreased signaling through the MAPK pathway.	xenograft + patients	266	
circMAPK14	circMAPK14‐175aa	Colorectal cancer		Tumor-suppressive	Competitive binding to MKK6. This results in decreased MAPK14 phosphorylation and leads to proteasome-dependent degradation of FOXC1.	xenograft + patients	267	
circMAP3K4	circMAP3K4‐455aa	Hepatocellular carcinoma		Oncogenic	Alteration of the nuclear distribution of AIF.	xenograft + patients	268	
circPLCE1	circPLCE1‐411	Colorectal carcinoma		Tumor-suppressive	Dissociation of the HSP90α/RPS3 complex, followed by proteasome-dependent degradation of RSP3. As a result, signaling through the NF‐κB pathway decreases.	xenograft + PDX + patients	269	
circPPP1R12A	cPPP1R12A-73aa	Colon cancer		Oncogenic	Promotion of Hippo-YAP signaling pathway.	xenograft + patients	270	
circSHPRH	SHPRH-146aa	Glioma		Tumor-suppressive	Promotion of proteasome-dependent degradation of PCNA.	xenograft + patients	271	
circSMO	SMO‐193aa	Glioblastoma		Oncogenic	Promotion of HH signaling pathway (Shh/Gli1/FUS/SMO‐193aa/SMO).	xenograft + patients	272	
circUBE4B	circUBE4B‐173aa	Esophageal squamous cell carcinoma		Oncogenic	Promotion of MAPK1 phosphorylation. This results in increased signaling through the MAPK pathway.	xenograft + patients	273	
circ0000437	CORO1C‐47aa	Endometrial cancer		Tumor-suppressive	Inhibition of VEGF expression.	xenograft + patients	274	
circPINTexon2	PINT87aa	Glioblastoma		Tumor-suppressive	Binding to PAF1. This results in the inhibition of the transcriptional elongation of multiple oncogenes.	xenograft + patients	209	
ecircCUX1	p113	Neuroblastoma		Oncogenic	Formation of the p113/ZRF1/BRD4 transcriptional regulatory complex.	xenograft + patients	275	
Bold: examples described in the text

Concluding remarks

In the last few years, it has become evident that the complexity of our genome vastly exceeds the simple organization into genetic units that code for proteins. Proteins are certainly the building blocks of cellular and organismal structures, but hundreds of thousands of non-coding RNAs are also at play, and in turn peptides of various lengths can be translated outside the canonical CDSs. Therefore, the intricacy of the coding vs non-coding interplay is progressively unraveling with mindboggling scenarios. As a paradigmatic example of the blurry boundary between what is coding and what is non-coding, we highlight long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT), a nuclear lincRNA under the transcriptional control of p53. LINC-PINT exerts an oncosuppressive role, although the molecular mechanism varies from cancer type to cancer type. In colon cancer, it works as a long non-coding RNA: it binds to the Polycomb Repressive Complex 2 and in so doing it prevents the transcription of pro-proliferation and pro-survival genes.208 Conversely, in glioblastoma, although it does not show coding capabilities per se, LINC-PINT undergoes back-splicing of exon 2. The EcircRNA that is generated, named circPINTexon2, contains an IRES and is translated into an 87-aa peptide. In turn, it is the PINT87aa ncPEP to be endowed with a tumor-suppressive role: in the nucleus, it directly interacts with RNA Polymerase II-Associated factor 1 (PAF1) and inhibits the elongation of the primary transcript of several oncogenes.209

In spite of such a variegated use of coding and non-coding elements, in Fig. 4 we attempt to categorize the modalities of expression and function of the coding and non-coding products derived from the same bifunctional gene: the protein and the non-coding RNA are co-expressed (e.g., in TNBC, hsa_circ_022705 is translated into FBXW7-185aa ncPEP and it also works as sponge for miR-197-3p162), or they are expressed in distinct tissues/physiopathologic conditions (e.g., LINC00665 works as ceRNA for miRNAs in several cancer types, with the exception of TNBC where it is instead translated into CIP2A-BP peptide163) (Fig. 4a). The protein and the non-coding RNA act in cis on their own gene, regulating each other’s expression and/or activity (e.g., ZEB-AS1 cis-NAT sustains ZEB1 protein expression115) (Fig. 4b). Alternatively, they act in trans on other genes or their products (e.g., MCM7 promotes DNA replication and miR-106b~25 cluster downregulates PTEN expression133) (Fig. 4c). Finally, their activities can be concordant (e.g., p53 protein and the CDS that encodes it140–142) or discordant (e.g., AKT3 protein vs AKT3-174aa ncPEP164).Fig. 4 The complexity of expression and function of the coding and non-coding products derived from the same bifunctional gene.

The coding product is represented as a generic orange protein and the non-coding product as a generic blue ncRNA. a Possible scenarios for gene expression. The protein and the ncRNA are expressed together in the same context (left), or separately in two different contexts (right). b Possible in cis regulatory mechanisms. The protein and the ncRNA positively or negatively regulate the gene from which they originate, or each other. c Possible in trans regulatory mechanisms. The protein and the ncRNA positively or negatively regulate downstream effectors (other genes, RNAs or proteins) that can be distinct or the same for both.

In addition, we highlight that concordant or discordant molecular activities result in a concordant or discordant impact on tumorigenesis: the protein and the non-coding RNA can be both tumor suppressors or both oncogenes, but oncogenic and tumor-suppressive activities can also coexist (see Fig. 5 for specific examples).Fig. 5 Concordant or discordant impact of the coding and non-coding products derived from the same bifunctional gene in cancer.

Graphical representation of the possible combinations of cancer-related functions of coding (orange) and non-coding (blue) partners. Upper left panel: both the coding and the non-coding products have tumor-suppressive properties. PTEN mRNA encodes the tumor suppressor PTEN protein and, due to its 3′UTR, it can sponge oncogenic miRNAs. Upper right panel: the coding product is a tumor suppressor, while the non-coding product is an oncogene. Zbtb7a pre-mRNA undergoes canonical splicing and generates a mature mRNA that encodes the Pokémon protein with tumor suppressor properties; the same pre-mRNA also undergoes back-splicing of exon 2, leading to the formation of oncogenic circPOK. Bottom left panel: the coding product is an oncogene, while the non-coding product is a tumor suppressor. AKT3 pre-mRNA is translated into AKT3 oncogenic protein, but exons 3–7 undergo back-splicing, leading to the production of a circRNA (hsa_circ_0017250) that exerts tumor-suppressive effects through its translation into the AKT3-174aa ncPEP. Bottom right panel: both the coding and the non-coding products have oncogenic properties. MCM7 pre-mRNA is spliced to produce a mature mRNA that is translated into the oncogenic MCM7 protein; in addition, intron 13 hosts oncogenic miR-106b~25 cluster. From a therapeutic point of view, the optimal approach is to enhance/restore tumor-suppressive activities (green “plus” symbol) and/or, on the other hand, abolish/inhibit oncogenic activities (red “minus” symbol). This is easier in the case of bifunctional genes whose products have concordant outputs, while it can be ineffective or even deleterious in the case of a discordant output.

How can we disentangle the specific role exerted by coding and non-coding products of the same genetic unit, when we face such a degree of molecular and biological complexity?

To ablate the genetic unit through classic homologous recombination-mediated knockout is a coarse approach that will most certainly lead to profoundly misleading results, due to the concomitant inactivation of two or more players. However, the knockout of the bifunctional gene can be coupled with the add-back of one of its functional products at the time. This strategy suffers from the limitation of triggering the expression of the added-back (non-)coding RNA at supra-physiological or under-physiological levels. Nevertheless, it helps define the function of each product per se, which should precede the study of functional cross-talks among multiple products.

Alternatively, more precise ways to remodel the genome can be used, such as CRISPR-mediated editing. For example, CRISPR technology allows to surgically mutagenize the MREs present in the 3′UTR of a given mRNA, preventing its ability to work as ceRNA. Nevertheless, pitfalls hide even behind these apparently “cleaner” genetic interventions. If the coding and the non-coding RNAs regulate each other’s expression, then the alteration of one will inevitably affect the other as well. Therefore, it will not be possible to establish whether the functional outcome is a direct or indirect consequence of the alteration introduced. Going back to the example mentioned above, the removal of MREs will certainly deprive the mRNA of its non-coding ceRNA activity in trans, but it will also have an effect in cis, as it will result in an increase in the stability/translation of the mRNA itself, and hence in the level of the corresponding protein, since it is no longer targeted by miRNAs.

Irrespectively of the approach used to study a bifunctional gene in vitro, we emphasize the importance of corroborating the obtained results with appropriate in vivo models. So far the in vivo characterization of non-canonical functions of coding and non-coding RNAs has been almost exclusively performed in xenograft models. Transgenic mouse models can be counted on one hand, while knockout mouse models are even fewer and all fall outside cancer research. For example, Masumoto et al.210 set up a knockout GEM to study the role played by LINC00961 and its encoded polypeptide SPAR (Small regulatory Polypeptide of Amino acid Response) in muscle regeneration. Xenografted animals are easy to handle, and they produce quite consistent results in a relatively short time. Nevertheless, we should rely on them just as a first readout of cell autonomous outcomes. To fully grasp the involvement of the most promising (non-)coding candidates on disease/cancer initiation, progression, and response to pharmacological treatment, it is then necessary to develop appropriate GEMs in immunocompetent hosts.91,211

Moving from basic to translational research, bifunctional genes offer concrete therapeutic opportunities. This rests on the flourishing interest in RNA-based drugs, which are under investigation in alternative to or in combination with “classical” chemical inhibitors of protein function and have gained full acceptance during COVID-19 emergency.212,213 Bifunctional genes that produce only tumor suppressors or only oncogenes are easier to deal with. By contrast, bifunctional genes that produce one tumor suppressor and one oncogene need to be approached with caution: we must avoid the unintended impairment of the tumor-suppressive activity or the boosting of the oncogenic activity caused by our intervention.

In conclusion, we show that the study of protein-coding and non-coding products, their functions and regulation is essential to understand many genetic units in our genome. We also propose that bifunctional genes should be classified as such, distinguishing them from only coding ones and only non-coding ones. However, we point out that much more functional validation is needed towards such classification, both in vitro and in vivo, using the appropriate technological tools for genetic manipulation currently available or to be developed in the foreseeable future. We cannot deny that some intricacies are so thick that may prove daunting or almost impossible to resolve. Nonetheless, we are confident that the widespread transcription and partly overlapping translation of our genome is paving the way for unprecedented opportunities of discovery, drug development and disease treatment.

Acknowledgements

We thank Maurizio S. Podda and all Poliseno lab members for helpful discussions. We acknowledge many investigators in the field whose primary data could not be cited. This work was supported by ISPRO-Istituto per lo Studio, la Prevenzione e la Rete Oncologica (institutional funding to L.P.). It was also partially supported by AIRC-Associazione Italiana Ricerca sul Cancro (IG #25694 to L.P.). P.P.P. has been supported by the Renown Foundation and the PTEN Research Foundation. Cartoons created with BioRender.com.

Author contributions

L.P. and P.P.P. conceptualized the review. M.L. gathered the information and created the figures. All authors contributed to writing and editing the text.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Laura Poliseno, Martina Lanza.
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References

1. CRICK F Central dogma of molecular biology Nature 1970 227 561 563 10.1038/227561a0 4913914
CRICK, F. Central dogma of molecular biology. Nature 227, 561–563 (1970).4913914 10.1038/227561a0
2. Strader LC The complexity of transferring genetic information Mol. Cell 2023 83 320 323 10.1016/j.molcel.2023.01.002 36736305
Strader, L. C. et al. The complexity of transferring genetic information. Mol. Cell 83, 320–323 (2023).36736305 10.1016/j.molcel.2023.01.002
3. Takahashi H Carninci P Widespread genome transcription: new possibilities for RNA therapies Biochem. Biophys. Res. Commun. 2014 452 294 301 10.1016/j.bbrc.2014.08.139 25193698
Takahashi, H. & Carninci, P. Widespread genome transcription: new possibilities for RNA therapies. Biochem. Biophys. Res. Commun. 452, 294–301 (2014).25193698 10.1016/j.bbrc.2014.08.139
4. Beermann J Piccoli M-T Viereck J Thum T Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches Physiol. Rev. 2016 96 1297 1325 10.1152/physrev.00041.2015 27535639
Beermann, J., Piccoli, M.-T., Viereck, J. & Thum, T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol. Rev. 96, 1297–1325 (2016).27535639 10.1152/physrev.00041.2015
5. Mattick JS Long non-coding RNAs: definitions, functions, challenges and recommendations Nat. Rev. Mol. Cell Biol. 2023 24 430 447 10.1038/s41580-022-00566-8 36596869
Mattick, J. S. et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat. Rev. Mol. Cell Biol. 24, 430–447 (2023).36596869 10.1038/s41580-022-00566-8
6. Oo JA Brandes RP Leisegang MS Long non-coding RNAs: novel regulators of cellular physiology and function Pflug. Arch. 2022 474 191 204 10.1007/s00424-021-02641-z
Oo, J. A., Brandes, R. P. & Leisegang, M. S. Long non-coding RNAs: novel regulators of cellular physiology and function. Pflug. Arch. 474, 191–204 (2022).10.1007/s00424-021-02641-z
7. Mattick JS A Kuhnian revolution in molecular biology: most genes in complex organisms express regulatory RNAs BioEssays 2023 45 e2300080 10.1002/bies.202300080 37318305
Mattick, J. S. A Kuhnian revolution in molecular biology: most genes in complex organisms express regulatory RNAs. BioEssays 45, e2300080 (2023).37318305 10.1002/bies.202300080
8. Sparber P Filatova A Khantemirova M Skoblov M The role of long non-coding RNAs in the pathogenesis of hereditary diseases BMC Med. Genomics 2019 12 42 10.1186/s12920-019-0487-6 30871545
Sparber, P., Filatova, A., Khantemirova, M. & Skoblov, M. The role of long non-coding RNAs in the pathogenesis of hereditary diseases. BMC Med. Genomics 12, 42 (2019).30871545 10.1186/s12920-019-0487-6
9. Chen Y Li Z Chen X Zhang S Long non-coding RNAs: from disease code to drug role Acta Pharm. Sin. B 2021 11 340 354 10.1016/j.apsb.2020.10.001 33643816
Chen, Y., Li, Z., Chen, X. & Zhang, S. Long non-coding RNAs: from disease code to drug role. Acta Pharm. Sin. B 11, 340–354 (2021).33643816 10.1016/j.apsb.2020.10.001
10. Shang R Lee S Senavirathne G Lai E C. microRNAs in action: biogenesis, function and regulation Nat. Rev. Genet. 2023 24 816 833 10.1038/s41576-023-00611-y 37380761
Shang, R., Lee, S., Senavirathne, G. & Lai, E. C. microRNAs in action: biogenesis, function and regulation. Nat. Rev. Genet. 24, 816–833 (2023).37380761 10.1038/s41576-023-00611-y
11. Morey C Avner P Employment opportunities for non-coding RNAs FEBS Lett. 2004 567 27 34 15165889
Morey, C. & Avner, P. Employment opportunities for non-coding RNAs. FEBS Lett. 567, 27–34 (2004).15165889
12. Zhang P Wu W Chen Q Chen M Non-coding RNAs and their integrated networks J. Integr. Bioinform. 2019 16 20190027 10.1515/jib-2019-0027 31301674
Zhang, P., Wu, W., Chen, Q. & Chen, M. Non-coding RNAs and their integrated networks. J. Integr. Bioinform. 16, 20190027 (2019).31301674 10.1515/jib-2019-0027
13. Zhang Z Zhang J Diao L Han L Small non-coding RNAs in human cancer: function, clinical utility, and characterization Oncogene 2021 40 1570 1577 10.1038/s41388-020-01630-3 33452456
Zhang, Z., Zhang, J., Diao, L. & Han, L. Small non-coding RNAs in human cancer: function, clinical utility, and characterization. Oncogene 40, 1570–1577 (2021).33452456 10.1038/s41388-020-01630-3
14. Xiong Q Zhang Y Li J Zhu Q Small non-coding RNAs in human cancer Genes 2022 13 2072 10.3390/genes13112072 36360311
Xiong, Q., Zhang, Y., Li, J. & Zhu, Q. Small non-coding RNAs in human cancer. Genes 13, 2072 (2022).36360311 10.3390/genes13112072
15. García-Vílchez R METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer Mol. Cancer 2023 22 119 10.1186/s12943-023-01809-8 37516825
García-Vílchez, R. et al. METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer. Mol. Cancer 22, 119 (2023).37516825 10.1186/s12943-023-01809-8
16. Lin Y Zheng J Lin D PIWI-interacting RNAs in human cancer Semin. Cancer Biol. 2021 75 15 28 10.1016/j.semcancer.2020.08.012 32877760
Lin, Y., Zheng, J. & Lin, D. PIWI-interacting RNAs in human cancer. Semin. Cancer Biol. 75, 15–28 (2021).32877760 10.1016/j.semcancer.2020.08.012
17. Ameres SL Zamore PD Diversifying microRNA sequence and function Nat. Rev. Mol. Cell Biol. 2013 14 475 488 10.1038/nrm3611 23800994
Ameres, S. L. & Zamore, P. D. Diversifying microRNA sequence and function. Nat. Rev. Mol. Cell Biol. 14, 475–488 (2013).23800994 10.1038/nrm3611
18. Michaels YS Precise tuning of gene expression levels in mammalian cells Nat. Commun. 2019 10 818 10.1038/s41467-019-08777-y 30778069
Michaels, Y. S. et al. Precise tuning of gene expression levels in mammalian cells. Nat. Commun. 10, 818 (2019).30778069 10.1038/s41467-019-08777-y
19. Cavallari I The miR-200 family of microRNAs: fine tuners of epithelial-mesenchymal transition and circulating cancer biomarkers Cancers 2021 13 5874 10.3390/cancers13235874 34884985
Cavallari, I. et al. The miR-200 family of microRNAs: fine tuners of epithelial-mesenchymal transition and circulating cancer biomarkers. Cancers 13, 5874 (2021).34884985 10.3390/cancers13235874
20. Ali Syeda Z Langden SSS Munkhzul C Lee M Song SJ Regulatory mechanism of microRNA expression in cancer Int. J. Mol. Sci. 2020 21 1723 10.3390/ijms21051723 32138313
Ali Syeda, Z., Langden, S. S. S., Munkhzul, C., Lee, M. & Song, S. J. Regulatory mechanism of microRNA expression in cancer. Int. J. Mol. Sci. 21, 1723 (2020).32138313 10.3390/ijms21051723
21. Peng Y Croce CM The role of microRNAs in human cancer Signal Transduct. Target. Ther. 2016 1 15004 10.1038/sigtrans.2015.4 29263891
Peng, Y. & Croce, C. M. The role of microRNAs in human cancer. Signal Transduct. Target. Ther. 1, 15004 (2016).29263891 10.1038/sigtrans.2015.4
22. Zhou K Liu M Cao Y New insight into microRNA functions in cancer: oncogene–microRNA–tumor suppressor gene network Front. Mol. Biosci. 2017 4 46 10.3389/fmolb.2017.00046 28736730
Zhou, K., Liu, M. & Cao, Y. New insight into microRNA functions in cancer: oncogene–microRNA–tumor suppressor gene network. Front. Mol. Biosci. 4, 46 (2017).28736730 10.3389/fmolb.2017.00046
23. Si W Shen J Zheng H Fan W The role and mechanisms of action of microRNAs in cancer drug resistance Clin. Epigenetics 2019 11 25 10.1186/s13148-018-0587-8 30744689
Si, W., Shen, J., Zheng, H. & Fan, W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin. Epigenetics 11, 25 (2019).30744689 10.1186/s13148-018-0587-8
24. Svoronos AA Engelman DM Slack FJ OncomiR or tumor suppressor? the duplicity of microRNAs in cancer Cancer Res 2016 76 3666 3670 10.1158/0008-5472.CAN-16-0359 27325641
Svoronos, A. A., Engelman, D. M. & Slack, F. J. OncomiR or tumor suppressor? the duplicity of microRNAs in cancer. Cancer Res. 76, 3666–3670 (2016).27325641 10.1158/0008-5472.CAN-16-0359
25. Cui M Circulating microRNAs in cancer: potential and challenge Front. Genet. 2019 10 626 10.3389/fgene.2019.00626 31379918
Cui, M. et al. Circulating microRNAs in cancer: potential and challenge. Front. Genet. 10, 626 (2019).31379918 10.3389/fgene.2019.00626
26. Smolarz B Durczyński A Romanowicz H Szyłło K Hogendorf P miRNAs in cancer (review of literature) Int. J. Mol. Sci. 2022 23 2805 10.3390/ijms23052805 35269947
Smolarz, B., Durczyński, A., Romanowicz, H., Szyłło, K. & Hogendorf, P. miRNAs in cancer (review of literature). Int. J. Mol. Sci. 23, 2805 (2022).35269947 10.3390/ijms23052805
27. El-Daly SM Gouhar SA Abd Elmageed ZY Circulating microRNAs as reliable tumor biomarkers: opportunities and challenges facing clinical application J. Pharm. Exp. Ther. 2023 384 35 51 10.1124/jpet.121.000896
El-Daly, S. M., Gouhar, S. A. & Abd Elmageed, Z. Y. Circulating microRNAs as reliable tumor biomarkers: opportunities and challenges facing clinical application. J. Pharm. Exp. Ther. 384, 35–51 (2023).10.1124/jpet.121.000896
28. Kim T Croce CM MicroRNA: trends in clinical trials of cancer diagnosis and therapy strategies Exp. Mol. Med. 2023 55 1314 1321 10.1038/s12276-023-01050-9 37430087
Kim, T. & Croce, C. M. MicroRNA: trends in clinical trials of cancer diagnosis and therapy strategies. Exp. Mol. Med. 55, 1314–1321 (2023).37430087 10.1038/s12276-023-01050-9
29. Salmena L Poliseno L Tay Y Kats L Pandolfi PP A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell 2011 146 353 358 10.1016/j.cell.2011.07.014 21802130
Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P. P. A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011).21802130 10.1016/j.cell.2011.07.014
30. Ala U Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments Proc. Natl. Acad. Sci. USA 2013 110 7154 7159 10.1073/pnas.1222509110 23536298
Ala, U. et al. Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments. Proc. Natl. Acad. Sci. USA 110, 7154–7159 (2013).23536298 10.1073/pnas.1222509110
31. Bosia C Pagnani A Zecchina R Modelling competing endogenous RNA networks PLoS One 2013 8 e66609 10.1371/journal.pone.0066609 23840508
Bosia, C., Pagnani, A. & Zecchina, R. Modelling competing endogenous RNA networks. PLoS One 8, e66609 (2013).23840508 10.1371/journal.pone.0066609
32. Figliuzzi M Marinari E De Martino A MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory Biophys. J. 2013 104 1203 1213 10.1016/j.bpj.2013.01.012 23473503
Figliuzzi, M., Marinari, E. & De Martino, A. MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. Biophys. J. 104, 1203–1213 (2013).23473503 10.1016/j.bpj.2013.01.012
33. Hausser J Zavolan M Identification and consequences of miRNA-target interactions—beyond repression of gene expression Nat. Rev. Genet. 2014 15 599 612 10.1038/nrg3765 25022902
Hausser, J. & Zavolan, M. Identification and consequences of miRNA-target interactions—beyond repression of gene expression. Nat. Rev. Genet. 15, 599–612 (2014).25022902 10.1038/nrg3765
34. Poliseno L Pandolfi PP PTEN ceRNA networks in human cancer Methods 2015 77-78 41 50 10.1016/j.ymeth.2015.01.013 25644446
Poliseno, L. & Pandolfi, P. P. PTEN ceRNA networks in human cancer. Methods 77-78, 41–50 (2015).25644446 10.1016/j.ymeth.2015.01.013
35. Bosia C RNAs competing for microRNAs mutually influence their fluctuations in a highly non-linear microRNA-dependent manner in single cells Genome Biol. 2017 18 37 10.1186/s13059-017-1162-x 28219439
Bosia, C. et al. RNAs competing for microRNAs mutually influence their fluctuations in a highly non-linear microRNA-dependent manner in single cells. Genome Biol. 18, 37 (2017).28219439 10.1186/s13059-017-1162-x
36. Chiu HS The number of titrated microRNA species dictates ceRNA regulation Nucleic Acids Res 2018 46 4354 4369 10.1093/nar/gky286 29684207
Chiu, H. S. et al. The number of titrated microRNA species dictates ceRNA regulation. Nucleic Acids Res. 46, 4354–4369 (2018).29684207 10.1093/nar/gky286
37. Dhawan A Mathematical modeling of ceRNA-based interactions Methods Mol. Biol. 2021 2324 105 114 10.1007/978-1-0716-1503-4_7 34165711
Dhawan, A. Mathematical modeling of ceRNA-based interactions. Methods Mol. Biol. 2324, 105–114 (2021).34165711 10.1007/978-1-0716-1503-4_7
38. Yang N Liu K Yang M Gao X ceRNAs in cancer: mechanism and functions in a comprehensive regulatory network J. Oncol. 2021 2021 4279039 10.1155/2021/4279039 34659409
Yang, N., Liu, K., Yang, M. & Gao, X. ceRNAs in cancer: mechanism and functions in a comprehensive regulatory network. J. Oncol. 2021, 4279039 (2021).34659409 10.1155/2021/4279039
39. Nitzan M Steiman-Shimony A Altuvia Y Biham O Margalit H Interactions between distant ceRNAs in regulatory networks Biophys. J. 2014 106 2254 2266 10.1016/j.bpj.2014.03.040 24853754
Nitzan, M., Steiman-Shimony, A., Altuvia, Y., Biham, O. & Margalit, H. Interactions between distant ceRNAs in regulatory networks. Biophys. J. 106, 2254–2266 (2014).24853754 10.1016/j.bpj.2014.03.040
40. Paci P Colombo T Farina L Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer BMC Syst. Biol. 2014 8 83 10.1186/1752-0509-8-83 25033876
Paci, P., Colombo, T. & Farina, L. Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer. BMC Syst. Biol. 8, 83 (2014).25033876 10.1186/1752-0509-8-83
41. Conte F Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer PLoS One 2017 12 e0171661 10.1371/journal.pone.0171661 28187158
Conte, F. et al. Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer. PLoS One 12, e0171661 (2017).28187158 10.1371/journal.pone.0171661
42. Zhang Y Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network Mol. Oncol. 2018 12 1429 1446 10.1002/1878-0261.12181 29464864
Zhang, Y. et al. Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network. Mol. Oncol. 12, 1429–1446 (2018).29464864 10.1002/1878-0261.12181
43. Qian D Integrated analysis of ceRNA network reveals prognostic and metastasis associated biomarkers in breast cancer Front. Oncol. 2021 11 670138 10.3389/fonc.2021.670138 34055638
Qian, D. et al. Integrated analysis of ceRNA network reveals prognostic and metastasis associated biomarkers in breast cancer. Front. Oncol. 11, 670138 (2021).34055638 10.3389/fonc.2021.670138
44. Chen J Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer BMC Cancer 2021 21 255 10.1186/s12885-021-07995-2 33750326
Chen, J. et al. Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer. BMC Cancer 21, 255 (2021).33750326 10.1186/s12885-021-07995-2
45. Xu J Xu J Liu X Jiang J The role of lncRNA-mediated ceRNA regulatory networks in pancreatic cancer Cell Death Discov. 2022 8 287 10.1038/s41420-022-01061-x 35697671
Xu, J., Xu, J., Liu, X. & Jiang, J. The role of lncRNA-mediated ceRNA regulatory networks in pancreatic cancer. Cell Death Discov. 8, 287 (2022).35697671 10.1038/s41420-022-01061-x
46. Chan J Tay Y Noncoding RNA:RNA regulatory networks in cancer Int. J. Mol. Sci. 2018 19 1310 10.3390/ijms19051310 29702599
Chan, J. & Tay, Y. Noncoding RNA:RNA regulatory networks in cancer. Int. J. Mol. Sci. 19, 1310 (2018).29702599 10.3390/ijms19051310
47. Anastasiadou E Jacob LS Slack FJ Non-coding RNA networks in cancer Nat. Rev. Cancer 2018 18 5 18 10.1038/nrc.2017.99 29170536
Anastasiadou, E., Jacob, L. S. & Slack, F. J. Non-coding RNA networks in cancer. Nat. Rev. Cancer 18, 5–18 (2018).29170536 10.1038/nrc.2017.99
48. Li Z LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations Nucleic Acids Res. 2023 51 D186 D191 10.1093/nar/gkac999 36330950
Li, Z. et al. LncBook 2.0: integrating human long non-coding RNAs with multi-omics annotations. Nucleic Acids Res. 51, D186–D191 (2023).36330950 10.1093/nar/gkac999
49. Nojima T Proudfoot NJ Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics Nat. Rev. Mol. Cell Biol. 2022 23 389 406 10.1038/s41580-021-00447-6 35079163
Nojima, T. & Proudfoot, N. J. Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics. Nat. Rev. Mol. Cell Biol. 23, 389–406 (2022).35079163 10.1038/s41580-021-00447-6
50. Hou J Zhang G Wang X Wang Y Wang K Functions and mechanisms of lncRNA MALAT1 in cancer chemotherapy resistance Biomark. Res. 2023 11 23 10.1186/s40364-023-00467-8 36829256
Hou, J., Zhang, G., Wang, X., Wang, Y. & Wang, K. Functions and mechanisms of lncRNA MALAT1 in cancer chemotherapy resistance. Biomark. Res. 11, 23 (2023).36829256 10.1186/s40364-023-00467-8
51. Ma L Bajic VB Zhang Z On the classification of long non-coding RNAs RNA Biol. 2013 10 924 933 10.4161/rna.24604
Ma, L., Bajic, V. B. & Zhang, Z. On the classification of long non-coding RNAs. RNA Biol. 10, 924–933 (2013).10.4161/rna.24604
52. Wang KC Chang HY Molecular mechanisms of long noncoding RNAs Mol. Cell 2011 43 904 914 10.1016/j.molcel.2011.08.018 21925379
Wang, K. C. & Chang, H. Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914 (2011).21925379 10.1016/j.molcel.2011.08.018
53. Li X Wu Z Fu X Han W lncRNAs: insights into their function and mechanics in underlying disorders Mutat. Res. Rev. Mutat. Res. 2014 762 1 21 10.1016/j.mrrev.2014.04.002 25485593
Li, X., Wu, Z., Fu, X. & Han, W. lncRNAs: insights into their function and mechanics in underlying disorders. Mutat. Res. Rev. Mutat. Res. 762, 1–21 (2014).25485593 10.1016/j.mrrev.2014.04.002
54. Zhang X Mechanisms and functions of long non-coding RNAs at multiple regulatory levels Int. J. Mol. Sci. 2019 20 5573 10.3390/ijms20225573 31717266
Zhang, X. et al. Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. Int. J. Mol. Sci. 20, 5573 (2019).31717266 10.3390/ijms20225573
55. Statello L Guo CJ Chen LL Huarte M Gene regulation by long non-coding RNAs and its biological functions Nat. Rev. Mol. Cell Biol. 2021 22 96 118 10.1038/s41580-020-00315-9 33353982
Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).33353982 10.1038/s41580-020-00315-9
56. Qian Y Shi L Luo Z Long non-coding RNAs in cancer: implications for diagnosis, prognosis, and therapy Front. Med. 2020 7 612393 10.3389/fmed.2020.612393
Qian, Y., Shi, L. & Luo, Z. Long non-coding RNAs in cancer: implications for diagnosis, prognosis, and therapy. Front. Med. 7, 612393 (2020).10.3389/fmed.2020.612393
57. Chen B Targeting non-coding RNAs to overcome cancer therapy resistance Signal Transduct. Target. Ther. 2022 7 121 10.1038/s41392-022-00975-3 35418578
Chen, B. et al. Targeting non-coding RNAs to overcome cancer therapy resistance. Signal Transduct. Target. Ther. 7, 121 (2022).35418578 10.1038/s41392-022-00975-3
58. Barczak W Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response Nat. Commun. 2023 14 1078 10.1038/s41467-023-36826-0 36841868
Barczak, W. et al. Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response. Nat. Commun. 14, 1078 (2023).36841868 10.1038/s41467-023-36826-0
59. Ransohoff JD Wei Y Khavari PA The functions and unique features of long intergenic non-coding RNA Nat. Rev. Mol. Cell Biol. 2018 19 143 157 10.1038/nrm.2017.104 29138516
Ransohoff, J. D., Wei, Y. & Khavari, P. A. The functions and unique features of long intergenic non-coding RNA. Nat. Rev. Mol. Cell Biol. 19, 143–157 (2018).29138516 10.1038/nrm.2017.104
60. Brockdorff N The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus Cell 1992 71 515 526 10.1016/0092-8674(92)90519-I 1423610
Brockdorff, N. et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992).1423610 10.1016/0092-8674(92)90519-I
61. Rinn JL Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs Cell 2007 129 1311 1323 10.1016/j.cell.2007.05.022 17604720
Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).17604720 10.1016/j.cell.2007.05.022
62. Hussen BM Role of lncRNA BANCR in human cancers: an updated review Front. Cell Dev. Biol. 2021 9 689992 10.3389/fcell.2021.689992 34409032
Hussen, B. M. et al. Role of lncRNA BANCR in human cancers: an updated review. Front. Cell Dev. Biol. 9, 689992 (2021).34409032 10.3389/fcell.2021.689992
63. Wen X Wu Y Lou Y Xia Y Yu X The roles of Linc-ROR in the regulation of cancer stem cells Transl. Oncol. 2023 28 101602 10.1016/j.tranon.2022.101602 36535192
Wen, X., Wu, Y., Lou, Y., Xia, Y. & Yu, X. The roles of Linc-ROR in the regulation of cancer stem cells. Transl. Oncol. 28, 101602 (2023).36535192 10.1016/j.tranon.2022.101602
64. Ghasemian M Babaahmadi-Rezaei H Khedri A Selvaraj C The oncogenic role of SAMMSON lncRNA in tumorigenesis: A comprehensive review with especial focus on melanoma J. Cell Mol. Med. 2023 27 3966 3973 10.1111/jcmm.17978 37772815
Ghasemian, M., Babaahmadi-Rezaei, H., Khedri, A. & Selvaraj, C. The oncogenic role of SAMMSON lncRNA in tumorigenesis: A comprehensive review with especial focus on melanoma. J. Cell Mol. Med. 27, 3966–3973 (2023).37772815 10.1111/jcmm.17978
65. Zhao S Zhang X Chen S Zhang S Natural antisense transcripts in the biological hallmarks of cancer: powerful regulators hidden in the dark J. Exp. Clin. Cancer Res. 2020 39 187 10.1186/s13046-020-01700-0 32928281
Zhao, S., Zhang, X., Chen, S. & Zhang, S. Natural antisense transcripts in the biological hallmarks of cancer: powerful regulators hidden in the dark. J. Exp. Clin. Cancer Res. 39, 187 (2020).32928281 10.1186/s13046-020-01700-0
66. Santos F Capela AM Mateus F Nóbrega-Pereira S & Bernardes de Jesus, B. Non-coding antisense transcripts: fine regulation of gene expression in cancer Comput. Struct. Biotechnol. J. 2022 20 5652 5660 10.1016/j.csbj.2022.10.009 36284703
Santos, F., Capela, A. M., Mateus, F. & Nóbrega-Pereira, S. & Bernardes de Jesus, B. Non-coding antisense transcripts: fine regulation of gene expression in cancer. Comput. Struct. Biotechnol. J. 20, 5652–5660 (2022).36284703 10.1016/j.csbj.2022.10.009
67. Sisu C GENCODE pseudogenes Methods Mol. Biol. 2021 2324 67 82 10.1007/978-1-0716-1503-4_5 34165709
Sisu, C. GENCODE pseudogenes. Methods Mol. Biol. 2324, 67–82 (2021).34165709 10.1007/978-1-0716-1503-4_5
68. Poliseno L Pseudogenes: newly discovered players in human cancer Sci. Signal. 2012 5 re5 10.1126/scisignal.2002858 22990117
Poliseno, L. Pseudogenes: newly discovered players in human cancer. Sci. Signal. 5, re5 (2012).22990117 10.1126/scisignal.2002858
69. Nakamura-García AK Espinal-Enríquez J Pseudogenes in cancer: state of the art Cancers 2023 15 4024 10.3390/cancers15164024 37627052
Nakamura-García, A. K. & Espinal-Enríquez, J. Pseudogenes in cancer: state of the art. Cancers 15, 4024 (2023).37627052 10.3390/cancers15164024
70. Poliseno L A coding-independent function of gene and pseudogene mRNAs regulates tumour biology Nature 2010 465 1033 1038 10.1038/nature09144 20577206
Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010).20577206 10.1038/nature09144
71. Poliseno L Marranci A Pandolfi PP Pseudogenes in human cancer Front. Med. 2015 2 68 10.3389/fmed.2015.00068
Poliseno, L., Marranci, A. & Pandolfi, P. P. Pseudogenes in human cancer. Front. Med. 2, 68 (2015).10.3389/fmed.2015.00068
72. Cheetham SW Faulkner GJ Dinger ME Overcoming challenges and dogmas to understand the functions of pseudogenes Nat. Rev. Genet. 2020 21 191 201 10.1038/s41576-019-0196-1 31848477
Cheetham, S. W., Faulkner, G. J. & Dinger, M. E. Overcoming challenges and dogmas to understand the functions of pseudogenes. Nat. Rev. Genet. 21, 191–201 (2020).31848477 10.1038/s41576-019-0196-1
73. Chen X Re-recognition of pseudogenes: from molecular to clinical applications Theranostics 2020 10 1479 1499 10.7150/thno.40659 32042317
Chen, X. et al. Re-recognition of pseudogenes: from molecular to clinical applications. Theranostics 10, 1479–1499 (2020).32042317 10.7150/thno.40659
74. Wang C Lin H Roles of piRNAs in transposon and pseudogene regulation of germline mRNAs and lncRNAs Genome Biol. 2021 22 27 10.1186/s13059-020-02221-x 33419460
Wang, C. & Lin, H. Roles of piRNAs in transposon and pseudogene regulation of germline mRNAs and lncRNAs. Genome Biol. 22, 27 (2021).33419460 10.1186/s13059-020-02221-x
75. Cooke SL Processed pseudogenes acquired somatically during cancer development Nat. Commun. 2014 5 3644 10.1038/ncomms4644 24714652
Cooke, S. L. et al. Processed pseudogenes acquired somatically during cancer development. Nat. Commun. 5, 3644 (2014).24714652 10.1038/ncomms4644
76. Stasiak M The world of pseudogenes: new diagnostic and therapeutic targets in cancers or still mystery molecules? Life 2021 11 1354 10.3390/life11121354 34947885
Stasiak, M. et al. The world of pseudogenes: new diagnostic and therapeutic targets in cancers or still mystery molecules? Life 11, 1354 (2021).34947885 10.3390/life11121354
77. Vitiello M Poliseno L CRISPR/Cas technologies applied to pseudogenes Methods Mol. Biol. 2021 2324 265 284 10.1007/978-1-0716-1503-4_17 34165721
Vitiello, M. & Poliseno, L. CRISPR/Cas technologies applied to pseudogenes. Methods Mol. Biol. 2324, 265–284 (2021).34165721 10.1007/978-1-0716-1503-4_17
78. Sun M Systematic functional interrogation of human pseudogenes using CRISPRi Genome Biol. 2021 22 240 10.1186/s13059-021-02464-2 34425866
Sun, M. et al. Systematic functional interrogation of human pseudogenes using CRISPRi. Genome Biol. 22, 240 (2021).34425866 10.1186/s13059-021-02464-2
79. Sisu C Pseudogenes as biomarkers and therapeutic targets in human cancers Methods Mol. Biol. 2021 2324 319 337 10.1007/978-1-0716-1503-4_20 34165724
Sisu, C. Pseudogenes as biomarkers and therapeutic targets in human cancers. Methods Mol. Biol. 2324, 319–337 (2021).34165724 10.1007/978-1-0716-1503-4_20
80. Jeck WR Circular RNAs are abundant, conserved, and associated with ALU repeats RNA 2013 19 141 157 10.1261/rna.035667.112 23249747
Jeck, W. R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 141–157 (2013).23249747 10.1261/rna.035667.112
81. Cheng D Wang J Dong Z Li X Cancer-related circular RNA: diverse biological functions Cancer Cell Int 2021 21 11 10.1186/s12935-020-01703-z 33407501
Cheng, D., Wang, J., Dong, Z. & Li, X. Cancer-related circular RNA: diverse biological functions. Cancer Cell Int. 21, 11 (2021).33407501 10.1186/s12935-020-01703-z
82. Liu CX Chen LL Circular RNAs: characterization, cellular roles, and applications Cell 2022 185 2016 2034 10.1016/j.cell.2022.04.021 35584701
Liu, C. X. & Chen, L. L. Circular RNAs: characterization, cellular roles, and applications. Cell 185, 2016–2034 (2022).35584701 10.1016/j.cell.2022.04.021
83. Feng XY New insight into circRNAs: characterization, strategies, and biomedical applications Exp. Hematol. Oncol. 2023 12 91 10.1186/s40164-023-00451-w 37828589
Feng, X. Y. et al. New insight into circRNAs: characterization, strategies, and biomedical applications. Exp. Hematol. Oncol. 12, 91 (2023).37828589 10.1186/s40164-023-00451-w
84. Tang X Review on circular RNAs and new insights into their roles in cancer Comput. Struct. Biotechnol. J. 2021 19 910 928 10.1016/j.csbj.2021.01.018 33598105
Tang, X. et al. Review on circular RNAs and new insights into their roles in cancer. Comput. Struct. Biotechnol. J. 19, 910–928 (2021).33598105 10.1016/j.csbj.2021.01.018
85. Ma S Kong S Wang F Ju S CircRNAs: biogenesis, functions, and role in drug-resistant tumours Mol. Cancer 2020 19 119 10.1186/s12943-020-01231-4 32758239
Ma, S., Kong, S., Wang, F. & Ju, S. CircRNAs: biogenesis, functions, and role in drug-resistant tumours. Mol. Cancer 19, 119 (2020).32758239 10.1186/s12943-020-01231-4
86. Xu T CircRNAs in anticancer drug resistance: recent advances and future potential Mol. Cancer 2020 19 127 10.1186/s12943-020-01240-3 32799866
Xu, T. et al. CircRNAs in anticancer drug resistance: recent advances and future potential. Mol. Cancer 19, 127 (2020).32799866 10.1186/s12943-020-01240-3
87. Kristensen LS Jakobsen T Hager H Kjems J The emerging roles of circRNAs in cancer and oncology Nat. Rev. Clin. Oncol. 2022 19 188 206 10.1038/s41571-021-00585-y 34912049
Kristensen, L. S., Jakobsen, T., Hager, H. & Kjems, J. The emerging roles of circRNAs in cancer and oncology. Nat. Rev. Clin. Oncol. 19, 188–206 (2022).34912049 10.1038/s41571-021-00585-y
88. Qi D Ke R Huang JH Wu E Forging the future of circRNA therapeutics: unleashing synthetic potential and conquering challenges Mol. Ther. Nucleic Acids 2023 33 42 43 10.1016/j.omtn.2023.06.002 37727443
Qi, D., Ke, R., Huang, J. H. & Wu, E. Forging the future of circRNA therapeutics: unleashing synthetic potential and conquering challenges. Mol. Ther. Nucleic Acids 33, 42–43 (2023).37727443 10.1016/j.omtn.2023.06.002
89. Huang D Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides Nature 2024 625 593 602 10.1038/s41586-023-06834-7 38093017
Huang, D. et al. Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides. Nature 625, 593–602 (2024).38093017 10.1038/s41586-023-06834-7
90. Villanueva MT Circular RNA vaccines expose cryptic peptides Nat. Rev. Drug Discov. 2024 23 103 103 10.1038/d41573-024-00013-7 38225388
Villanueva, M. T. Circular RNA vaccines expose cryptic peptides. Nat. Rev. Drug Discov. 23, 103–103 (2024).38225388 10.1038/d41573-024-00013-7
91. Patton EE Melanoma models for the next generation of therapies Cancer Cell 2021 39 610 631 10.1016/j.ccell.2021.01.011 33545064
Patton, E. E. et al. Melanoma models for the next generation of therapies. Cancer Cell 39, 610–631 (2021).33545064 10.1016/j.ccell.2021.01.011
92. Zhong L Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives Signal Transduct. Target. Ther. 2021 6 201 10.1038/s41392-021-00572-w 34054126
Zhong, L. et al. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Signal Transduct. Target. Ther. 6, 201 (2021).34054126 10.1038/s41392-021-00572-w
93. Jin S Emerging new therapeutic antibody derivatives for cancer treatment Signal Transduct. Target. Ther. 2022 7 39 10.1038/s41392-021-00868-x 35132063
Jin, S. et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct. Target. Ther. 7, 39 (2022).35132063 10.1038/s41392-021-00868-x
94. Chen J Pervasive functional translation of noncanonical human open reading frames Science 2020 367 1140 1146 10.1126/science.aay0262 32139545
Chen, J. et al. Pervasive functional translation of noncanonical human open reading frames. Science 367, 1140–1146 (2020).32139545 10.1126/science.aay0262
95. Wei LH Guo JU Coding functions of “noncoding” RNAs Science 2020 367 1074 1075 10.1126/science.aba6117 32139529
Wei, L. H. & Guo, J. U. Coding functions of “noncoding” RNAs. Science 367, 1074–1075 (2020).32139529 10.1126/science.aba6117
96. Lee DSM Disrupting upstream translation in mRNAs is associated with human disease Nat. Commun. 2021 12 1515 10.1038/s41467-021-21812-1 33750777
Lee, D. S. M. et al. Disrupting upstream translation in mRNAs is associated with human disease. Nat. Commun. 12, 1515 (2021).33750777 10.1038/s41467-021-21812-1
97. Hofman DA Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma Mol. Cell 2024 84 261 276.e18 10.1016/j.molcel.2023.12.003 38176414
Hofman, D. A. et al. Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma. Mol. Cell 84, 261–276.e18 (2024).38176414 10.1016/j.molcel.2023.12.003
98. Delaidelli A Oliveira de Santis J Sorensen PH Actions speak louder than ORFs: A non-canonical microprotein promotes medulloblastoma oncogenesis Mol. Cell 2024 84 188 190 10.1016/j.molcel.2023.12.027 38242097
Delaidelli, A., Oliveira de Santis, J. & Sorensen, P. H. Actions speak louder than ORFs: A non-canonical microprotein promotes medulloblastoma oncogenesis. Mol. Cell 84, 188–190 (2024).38242097 10.1016/j.molcel.2023.12.027
99. Hubé F Francastel C Coding and non-coding RNAs, the frontier has never been so blurred Front. Genet. 2018 9 140 10.3389/fgene.2018.00140 29720998
Hubé, F. & Francastel, C. Coding and non-coding RNAs, the frontier has never been so blurred. Front. Genet. 9, 140 (2018).29720998 10.3389/fgene.2018.00140
100. Matlin AJ Clark F Smith CWJ Understanding alternative splicing: towards a cellular code Nat. Rev. Mol. Cell Biol. 2005 6 386 398 10.1038/nrm1645 15956978
Matlin, A. J., Clark, F. & Smith, C. W. J. Understanding alternative splicing: towards a cellular code. Nat. Rev. Mol. Cell Biol. 6, 386–398 (2005).15956978 10.1038/nrm1645
101. Sammeth M Foissac S Guigó R A general definition and nomenclature for alternative splicing events PLoS Comput. Biol. 2008 4 e1000147 10.1371/journal.pcbi.1000147 18688268
Sammeth, M., Foissac, S. & Guigó, R. A general definition and nomenclature for alternative splicing events. PLoS Comput. Biol. 4, e1000147 (2008).18688268 10.1371/journal.pcbi.1000147
102. Liu Q Fang L Wu C Alternative splicing and isoforms: from mechanisms to diseases Genes 2022 13 401 10.3390/genes13030401 35327956
Liu, Q., Fang, L. & Wu, C. Alternative splicing and isoforms: from mechanisms to diseases. Genes 13, 401 (2022).35327956 10.3390/genes13030401
103. Dhamija S Menon MB Non-coding transcript variants of protein-coding genes—what are they good for? RNA Biol. 2018 15 1025 1031 30146915
Dhamija, S. & Menon, M. B. Non-coding transcript variants of protein-coding genes—what are they good for? RNA Biol. 15, 1025–1031 (2018).30146915
104. Yan Y Steroid receptor RNA activator protein (SRAP): a potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast cancer patients Breast Cancer Res. 2009 11 R67 10.1186/bcr2359 19740422
Yan, Y. et al. Steroid receptor RNA activator protein (SRAP): a potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast cancer patients. Breast Cancer Res. 11, R67 (2009).19740422 10.1186/bcr2359
105. KAWASHIMA H A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: expression in prostate cancer cells and enhancement of androgen receptor activity Biochem. J. 2003 369 163 171 10.1042/bj20020743 12350225
KAWASHIMA, H. et al. A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: expression in prostate cancer cells and enhancement of androgen receptor activity. Biochem. J. 369, 163–171 (2003).12350225 10.1042/bj20020743
106. Hube F Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines DNA Cell Biol. 2006 25 418 428 10.1089/dna.2006.25.418 16848684
Hube, F. et al. Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines. DNA Cell Biol. 25, 418–428 (2006).16848684 10.1089/dna.2006.25.418
107. Hong CH Ho JC Lee CH Steroid receptor RNA activator, a long noncoding RNA, activates p38, facilitates epithelial-mesenchymal transformation, and mediates experimental melanoma metastasis J. Invest. Dermatol. 2020 140 1355 1363.e1 10.1016/j.jid.2019.09.028 31945347
Hong, C. H., Ho, J. C. & Lee, C. H. Steroid receptor RNA activator, a long noncoding RNA, activates p38, facilitates epithelial-mesenchymal transformation, and mediates experimental melanoma metastasis. J. Invest. Dermatol. 140, 1355–1363.e1 (2020).31945347 10.1016/j.jid.2019.09.028
108. Allen PB Kwon YG Nairn AC Greengard P Isolation and characterization of PNUTS, a putative protein phosphatase 1 nuclear targeting subunit J. Biol. Chem. 1998 273 4089 4095 10.1074/jbc.273.7.4089 9461602
Allen, P. B., Kwon, Y. G., Nairn, A. C. & Greengard, P. Isolation and characterization of PNUTS, a putative protein phosphatase 1 nuclear targeting subunit. J. Biol. Chem. 273, 4089–4095 (1998).9461602 10.1074/jbc.273.7.4089
109. Landsverk HB Kirkhus M Bollen M Küntziger T Collas P PNUTS enhances in vitro chromosome decondensation in a PP1-dependent manner Biochem. J. 2005 390 709 717 10.1042/BJ20050678 15907195
Landsverk, H. B., Kirkhus, M., Bollen, M., Küntziger, T. & Collas, P. PNUTS enhances in vitro chromosome decondensation in a PP1-dependent manner. Biochem. J. 390, 709–717 (2005).15907195 10.1042/BJ20050678
110. Landsverk HB The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response EMBO Rep. 2010 11 868 875 10.1038/embor.2010.134 20890310
Landsverk, H. B. et al. The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response. EMBO Rep. 11, 868–875 (2010).20890310 10.1038/embor.2010.134
111. Grelet S A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression Nat. Cell Biol. 2017 19 1105 1115 10.1038/ncb3595 28825698
Grelet, S. et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat. Cell Biol. 19, 1105–1115 (2017).28825698 10.1038/ncb3595
112. Guarnerio J Intragenic antagonistic roles of protein and circRNA in tumorigenesis Cell Res. 2019 29 628 640 10.1038/s41422-019-0192-1 31209250
Guarnerio, J. et al. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 29, 628–640 (2019).31209250 10.1038/s41422-019-0192-1
113. Guarnerio J A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells Cancer Discov. 2015 5 396 409 10.1158/2159-8290.CD-14-1022 25614485
Guarnerio, J. et al. A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells. Cancer Discov. 5, 396–409 (2015).25614485 10.1158/2159-8290.CD-14-1022
114. Wu HT Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer J. Transl. Med 2020 18 51 10.1186/s12967-020-02240-z 32014049
Wu, H. T. et al. Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer. J. Transl. Med. 18, 51 (2020).32014049 10.1186/s12967-020-02240-z
115. Su W Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer Mol. Cancer 2017 16 142 10.1186/s12943-017-0711-y 28830551
Su, W. et al. Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer. Mol. Cancer 16, 142 (2017).28830551 10.1186/s12943-017-0711-y
116. Burk U A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells EMBO Rep. 2008 9 582 589 10.1038/embor.2008.74 18483486
Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).18483486 10.1038/embor.2008.74
117. Ghafouri-Fard S A review on the role of ZEB1-AS1 in human disorders Pathol. Res. Pr. 2023 245 154486 10.1016/j.prp.2023.154486
Ghafouri-Fard, S. et al. A review on the role of ZEB1-AS1 in human disorders. Pathol. Res. Pr. 245, 154486 (2023).10.1016/j.prp.2023.154486
118. Guo Z Cao Q Zhao Z Song C Biogenesis, features, functions, and disease relationships of a specific circular RNA: CDR1as Aging Dis. 2020 11 1009 10.14336/AD.2019.0920 32765960
Guo, Z., Cao, Q., Zhao, Z. & Song, C. Biogenesis, features, functions, and disease relationships of a specific circular RNA: CDR1as. Aging Dis. 11, 1009 (2020).32765960 10.14336/AD.2019.0920
119. Hansen TB miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA EMBO J. 2011 30 4414 4422 10.1038/emboj.2011.359 21964070
Hansen, T. B. et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 30, 4414–4422 (2011).21964070 10.1038/emboj.2011.359
120. Ulitsky I Shkumatava A Jan CH Sive H Bartel DP Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution Cell 2011 147 1537 1550 10.1016/j.cell.2011.11.055 22196729
Ulitsky, I., Shkumatava, A., Jan, C. H., Sive, H. & Bartel, D. P. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147, 1537–1550 (2011).22196729 10.1016/j.cell.2011.11.055
121. Memczak S Circular RNAs are a large class of animal RNAs with regulatory potency Nature 2013 495 333 338 10.1038/nature11928 23446348
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).23446348 10.1038/nature11928
122. Hansen TB Natural RNA circles function as efficient microRNA sponges Nature 2013 495 384 388 10.1038/nature11993 23446346
Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).23446346 10.1038/nature11993
123. Piwecka M Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function Science 2017 357 eaam8526 10.1126/science.aam8526 28798046
Piwecka, M. et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357, eaam8526 (2017).28798046 10.1126/science.aam8526
124. Kleaveland B Shi CY Stefano J Bartel DP A network of noncoding regulatory RNAs acts in the mammalian brain Cell 2018 174 350 362.e17 10.1016/j.cell.2018.05.022 29887379
Kleaveland, B., Shi, C. Y., Stefano, J. & Bartel, D. P. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174, 350–362.e17 (2018).29887379 10.1016/j.cell.2018.05.022
125. Kristensen LS Spatial expression analyses of the putative oncogene ciRS-7 in cancer reshape the microRNA sponge theory Nat. Commun. 2020 11 4551 10.1038/s41467-020-18355-2 32917870
Kristensen, L. S. et al. Spatial expression analyses of the putative oncogene ciRS-7 in cancer reshape the microRNA sponge theory. Nat. Commun. 11, 4551 (2020).32917870 10.1038/s41467-020-18355-2
126. Mecozzi N Vera O Karreth FA Squaring the circle: circRNAs in melanoma Oncogene 2021 40 5559 5566 10.1038/s41388-021-01977-1 34331015
Mecozzi, N., Vera, O. & Karreth, F. A. Squaring the circle: circRNAs in melanoma. Oncogene 40, 5559–5566 (2021).34331015 10.1038/s41388-021-01977-1
127. Lou J Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit gliomagenesis Mol. Cancer 2020 19 138 10.1186/s12943-020-01253-y 32894144
Lou, J. et al. Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit gliomagenesis. Mol. Cancer 19, 138 (2020).32894144 10.1186/s12943-020-01253-y
128. Hanniford D Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis Cancer Cell 2020 37 55 70.e15 10.1016/j.ccell.2019.12.007 31935372
Hanniford, D. et al. Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis. Cancer Cell 37, 55–70.e15 (2020).31935372 10.1016/j.ccell.2019.12.007
129. Boivin V Deschamps-Francoeur G Scott MS Protein coding genes as hosts for noncoding RNA expression Semin. Cell Dev. Biol. 2018 75 3 12 10.1016/j.semcdb.2017.08.016 28811264
Boivin, V., Deschamps-Francoeur, G. & Scott, M. S. Protein coding genes as hosts for noncoding RNA expression. Semin. Cell Dev. Biol. 75, 3–12 (2018).28811264 10.1016/j.semcdb.2017.08.016
130. Liu B Shyr Y Cai J Liu Q Interplay between miRNAs and host genes and their role in cancer Brief. Funct. Genomics 2019 18 255 266 10.1093/bfgp/elz002
Liu, B., Shyr, Y., Cai, J. & Liu, Q. Interplay between miRNAs and host genes and their role in cancer. Brief. Funct. Genomics 18, 255–266 (2019).10.1093/bfgp/elz002
131. Zeidler M Hüttenhofer A Kress M Kummer KK Intragenic microRNAs autoregulate their host genes in both direct and indirect ways — a cross-species analysis Cells 2020 9 232 10.3390/cells9010232 31963421
Zeidler, M., Hüttenhofer, A., Kress, M. & Kummer, K. K. Intragenic microRNAs autoregulate their host genes in both direct and indirect ways — a cross-species analysis. Cells 9, 232 (2020).31963421 10.3390/cells9010232
132. Wong ACH Rasko JEJ Splice and dice: intronic microRNAs, splicing and cancer Biomedicines 2021 9 1268 10.3390/biomedicines9091268 34572454
Wong, A. C. H. & Rasko, J. E. J. Splice and dice: intronic microRNAs, splicing and cancer. Biomedicines 9, 1268 (2021).34572454 10.3390/biomedicines9091268
133. Poliseno L Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation Sci. Signal. 2010 3 ra29 10.1126/scisignal.2000594 20388916
Poliseno, L. et al. Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci. Signal. 3, ra29 (2010).20388916 10.1126/scisignal.2000594
134. Blume S Inhibition of tumorigenicity by the 5′-untranslated RNA of the human c-myc P0 transcript Exp. Cell Res. 2003 288 131 142 10.1016/S0014-4827(03)00182-4 12878165
Blume, S. et al. Inhibition of tumorigenicity by the 5′-untranslated RNA of the human c-myc P0 transcript. Exp. Cell Res. 288, 131–142 (2003).12878165 10.1016/S0014-4827(03)00182-4
135. McMahon SB MYC and the control of apoptosis Cold Spring Harb. Perspect. Med. 2014 4 a014407 10.1101/cshperspect.a014407 24985130
McMahon, S. B. MYC and the control of apoptosis. Cold Spring Harb. Perspect. Med. 4, a014407 (2014).24985130 10.1101/cshperspect.a014407
136. Apte RS Chen DS Ferrara N VEGF in signaling and disease: beyond discovery and development Cell 2019 176 1248 1264 10.1016/j.cell.2019.01.021 30849371
Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).30849371 10.1016/j.cell.2019.01.021
137. Masuda K A novel tumor-promoting function residing in the 5′ non-coding region of vascular endothelial growth factor mRNA PLoS Med 2008 5 e94 10.1371/journal.pmed.0050094 18494554
Masuda, K. et al. A novel tumor-promoting function residing in the 5′ non-coding region of vascular endothelial growth factor mRNA. PLoS Med. 5, e94 (2008).18494554 10.1371/journal.pmed.0050094
138. Hernández Borrero LJ El-Deiry WS Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting Biochim. Biophys. Acta Rev. Cancer 2021 1876 188556 10.1016/j.bbcan.2021.188556 33932560
Hernández Borrero, L. J. & El-Deiry, W. S. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim. Biophys. Acta Rev. Cancer 1876, 188556 (2021).33932560 10.1016/j.bbcan.2021.188556
139. Kung CP Weber JD It’s getting complicated — a fresh look at p53-MDM2-ARF triangle in tumorigenesis and cancer therapy Front. Cell Dev. Biol. 2022 10 818744 10.3389/fcell.2022.818744 35155432
Kung, C. P. & Weber, J. D. It’s getting complicated — a fresh look at p53-MDM2-ARF triangle in tumorigenesis and cancer therapy. Front. Cell Dev. Biol. 10, 818744 (2022).35155432 10.3389/fcell.2022.818744
140. Candeias MM p53 mRNA controls p53 activity by managing Mdm2 functions Nat. Cell Biol. 2008 10 1098 1105 10.1038/ncb1770 19160491
Candeias, M. M. et al. p53 mRNA controls p53 activity by managing Mdm2 functions. Nat. Cell Biol. 10, 1098–1105 (2008).19160491 10.1038/ncb1770
141. Naski N The p53 mRNA-Mdm2 interaction Cell Cycle 2009 8 31 34 10.4161/cc.8.1.7326 19106616
Naski, N. et al. The p53 mRNA-Mdm2 interaction. Cell Cycle 8, 31–34 (2009).19106616 10.4161/cc.8.1.7326
142. Gajjar M The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage Cancer Cell 2012 21 25 35 10.1016/j.ccr.2011.11.016 22264786
Gajjar, M. et al. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage. Cancer Cell 21, 25–35 (2012).22264786 10.1016/j.ccr.2011.11.016
143. Karakostis K Fåhraeus R Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures BMC Cancer 2019 19 915 10.1186/s12885-019-6118-y 31519161
Karakostis, K. & Fåhraeus, R. Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures. BMC Cancer 19, 915 (2019).31519161 10.1186/s12885-019-6118-y
144. Ivanyi-Nagy R The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis Elife 2018 7 e40037 10.7554/eLife.40037 30355447
Ivanyi-Nagy, R. et al. The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis. Elife 7, e40037 (2018).30355447 10.7554/eLife.40037
145. De Paolo R Differential impact of BRAFV600E isoforms on tumorigenesis in a zebrafish model of melanoma Cell Biosci. 2023 13 121 10.1186/s13578-023-01064-w 37393328
De Paolo, R. et al. Differential impact of BRAFV600E isoforms on tumorigenesis in a zebrafish model of melanoma. Cell Biosci. 13, 121 (2023).37393328 10.1186/s13578-023-01064-w
146. Mayr C What are 3′ UTRs doing? Cold Spring Harb. Perspect. Biol. 2019 11 a034728 10.1101/cshperspect.a034728 30181377
Mayr, C. What are 3′ UTRs doing? Cold Spring Harb. Perspect. Biol. 11, a034728 (2019).30181377 10.1101/cshperspect.a034728
147. Chan JJ Tabatabaeian H Tay Y 3′UTR heterogeneity and cancer progression Trends Cell Biol. 2023 33 568 582 10.1016/j.tcb.2022.10.001 36372614
Chan, J. J., Tabatabaeian, H. & Tay, Y. 3′UTR heterogeneity and cancer progression. Trends Cell Biol. 33, 568–582 (2023).36372614 10.1016/j.tcb.2022.10.001
148. Zheng T CXCR4 3′UTR functions as a ceRNA in promoting metastasis, proliferation and survival of MCF-7 cells by regulating miR-146a activity Eur. J. Cell Biol. 2015 94 458 469 10.1016/j.ejcb.2015.05.010 26095299
Zheng, T. et al. CXCR4 3′UTR functions as a ceRNA in promoting metastasis, proliferation and survival of MCF-7 cells by regulating miR-146a activity. Eur. J. Cell Biol. 94, 458–469 (2015).26095299 10.1016/j.ejcb.2015.05.010
149. Lee YR Chen M Pandolfi PP The functions and regulation of the PTEN tumour suppressor: New modes and prospects Nat. Rev. Mol. Cell Biol. 2018 19 547 562 10.1038/s41580-018-0015-0 29858604
Lee, Y. R., Chen, M. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor: New modes and prospects. Nat. Rev. Mol. Cell Biol. 19, 547–562 (2018).29858604 10.1038/s41580-018-0015-0
150. Tay Y Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs Cell 2011 147 344 357 10.1016/j.cell.2011.09.029 22000013
Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).22000013 10.1016/j.cell.2011.09.029
151. Karreth FA In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma Cell 2011 147 382 395 10.1016/j.cell.2011.09.032 22000016
Karreth, F. A. et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395 (2011).22000016 10.1016/j.cell.2011.09.032
152. Lee DY Expression of versican 3′-untranslated region modulates endogenous microRNA functions PLoS One 2010 5 e13599 10.1371/journal.pone.0013599 21049042
Lee, D. Y. et al. Expression of versican 3′-untranslated region modulates endogenous microRNA functions. PLoS One 5, e13599 (2010).21049042 10.1371/journal.pone.0013599
153. Sumazin P An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma Cell 2011 147 370 381 10.1016/j.cell.2011.09.041 22000015
Sumazin, P. et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370–381 (2011).22000015 10.1016/j.cell.2011.09.041
154. Zarringhalam K Identification of competing endogenous RNAs of the tumor suppressor gene PTEN: A probabilistic approach Sci. Rep. 2017 7 7755 10.1038/s41598-017-08209-1 28798471
Zarringhalam, K. et al. Identification of competing endogenous RNAs of the tumor suppressor gene PTEN: A probabilistic approach. Sci. Rep. 7, 7755 (2017).28798471 10.1038/s41598-017-08209-1
155. Roquid KAR Alcantara KMM Garcia RL Identification and validation of mRNA 3′untranslated regions of DNMT3B and TET3 as novel competing endogenous RNAs of the tumor suppressor PTEN Int. J. Oncol. 2020 56 544 558 31894272
Roquid, K. A. R., Alcantara, K. M. M. & Garcia, R. L. Identification and validation of mRNA 3′untranslated regions of DNMT3B and TET3 as novel competing endogenous RNAs of the tumor suppressor PTEN. Int. J. Oncol. 56, 544–558 (2020).31894272
156. Park HJ 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk Nat. Genet. 2018 50 783 789 10.1038/s41588-018-0118-8 29785014
Park, H. J. et al. 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk. Nat. Genet. 50, 783–789 (2018).29785014 10.1038/s41588-018-0118-8
157. Tan X The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network J. Clin. Invest. 2018 128 1267 1282 10.1172/JCI97225 29324442
Tan, X. et al. The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J. Clin. Invest. 128, 1267–1282 (2018).29324442 10.1172/JCI97225
158. Caramel J A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma Cancer Cell 2013 24 466 480 10.1016/j.ccr.2013.08.018 24075834
Caramel, J. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24, 466–480 (2013).24075834 10.1016/j.ccr.2013.08.018
159. Xu J The mRNA related ceRNA–ceRNA landscape and significance across 20 major cancer types Nucleic Acids Res 2015 43 8169 8182 10.1093/nar/gkv853 26304537
Xu, J. et al. The mRNA related ceRNA–ceRNA landscape and significance across 20 major cancer types. Nucleic Acids Res. 43, 8169–8182 (2015).26304537 10.1093/nar/gkv853
160. Chiu HS High-throughput validation of ceRNA regulatory networks BMC Genomics 2017 18 418 10.1186/s12864-017-3790-7 28558729
Chiu, H. S. et al. High-throughput validation of ceRNA regulatory networks. BMC Genomics 18, 418 (2017).28558729 10.1186/s12864-017-3790-7
161. Xu X Gain of chromosome 1q perturbs a competitive endogenous RNA network to promote melanoma metastasis Cancer Res 2022 82 3016 3031 10.1158/0008-5472.CAN-22-0283 36052492
Xu, X. et al. Gain of chromosome 1q perturbs a competitive endogenous RNA network to promote melanoma metastasis. Cancer Res. 82, 3016–3031 (2022).36052492 10.1158/0008-5472.CAN-22-0283
162. Ye F circFBXW7 inhibits malignant progression by sponging miR-197-3p and encoding a 185-aa protein in triple-negative breast cancer Mol. Ther. Nucleic Acids 2019 18 88 98 10.1016/j.omtn.2019.07.023 31536884
Ye, F. et al. circFBXW7 inhibits malignant progression by sponging miR-197-3p and encoding a 185-aa protein in triple-negative breast cancer. Mol. Ther. Nucleic Acids 18, 88–98 (2019).31536884 10.1016/j.omtn.2019.07.023
163. Zhong C Xie Z Shen J Jia Y Duan S LINC00665: an emerging biomarker for cancer diagnostics and therapeutics Cells 2022 11 1540 10.3390/cells11091540 35563845
Zhong, C., Xie, Z., Shen, J., Jia, Y. & Duan, S. LINC00665: an emerging biomarker for cancer diagnostics and therapeutics. Cells 11, 1540 (2022).35563845 10.3390/cells11091540
164. Xia X A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent kinase-1 Mol. Cancer 2019 18 131 10.1186/s12943-019-1056-5 31470874
Xia, X. et al. A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent kinase-1. Mol. Cancer 18, 131 (2019).31470874 10.1186/s12943-019-1056-5
165. Huang X Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression Mol. Cancer 2019 18 71 10.1186/s12943-019-0969-3 30927924
Huang, X. et al. Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Mol. Cancer 18, 71 (2019).30927924 10.1186/s12943-019-0969-3
166. Zhou B Translation of noncoding RNAs and cancer Cancer Lett. 2021 497 89 99 10.1016/j.canlet.2020.10.002 33038492
Zhou, B. et al. Translation of noncoding RNAs and cancer. Cancer Lett. 497, 89–99 (2021).33038492 10.1016/j.canlet.2020.10.002
167. Xing J Liu H Jiang W Wang L LncRNA-encoded peptide: functions and predicting methods Front. Oncol. 2021 10 622294 10.3389/fonc.2020.622294 33520729
Xing, J., Liu, H., Jiang, W. & Wang, L. LncRNA-encoded peptide: functions and predicting methods. Front. Oncol. 10, 622294 (2021).33520729 10.3389/fonc.2020.622294
168. Zhang Y Wang X Hu C Yi H Shiny transcriptional junk: lncRNA-derived peptides in cancers and immune responses Life Sci. 2023 316 121434 10.1016/j.lfs.2023.121434 36706831
Zhang, Y., Wang, X., Hu, C. & Yi, H. Shiny transcriptional junk: lncRNA-derived peptides in cancers and immune responses. Life Sci. 316, 121434 (2023).36706831 10.1016/j.lfs.2023.121434
169. Liu H ncEP: a manually curated database for experimentally validated ncRNA-encoded proteins or peptides J. Mol. Biol. 2020 432 3364 3368 10.1016/j.jmb.2020.02.022 32105730
Liu, H. et al. ncEP: a manually curated database for experimentally validated ncRNA-encoded proteins or peptides. J. Mol. Biol. 432, 3364–3368 (2020).32105730 10.1016/j.jmb.2020.02.022
170. Dragomir MP Funcpep: a database of functional peptides encoded by non-coding rnas Noncoding RNA 2020 6 41 32977531
Dragomir, M. P. et al. Funcpep: a database of functional peptides encoded by non-coding rnas. Noncoding RNA 6, 41 (2020).32977531
171. Li J Liu C Coding or noncoding, the converging concepts of RNAs Front. Genet. 2019 10 496 10.3389/fgene.2019.00496 31178900
Li, J. & Liu, C. Coding or noncoding, the converging concepts of RNAs. Front. Genet. 10, 496 (2019).31178900 10.3389/fgene.2019.00496
172. Fang J Morsalin S Rao VN Reddy E Shyam P Decoding of non-coding DNA and non-coding RNA: pri-micro RNA-encoded novel peptides regulate migration of cancer cells J. Pharm. Sci. Pharm. 2017 3 23 27 10.1166/jpsp.2017.1070
Fang, J., Morsalin, S., Rao, V.N., Reddy, E. & Shyam, P. Decoding of non-coding DNA and non-coding RNA: pri-micro RNA-encoded novel peptides regulate migration of cancer cells. J. Pharm. Sci. Pharm. 3, 23–27 (2017).10.1166/jpsp.2017.1070
173. Guo B Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression EMBO J. 2020 39 e102190 10.15252/embj.2019102190 31755573
Guo, B. et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. EMBO J. 39, e102190 (2020).31755573 10.15252/embj.2019102190
174. Attalla S Taifour T Bui T Muller W Insights from transgenic mouse models of PyMT-induced breast cancer: Recapitulating human breast cancer progression in vivo Oncogene 2021 40 475 491 10.1038/s41388-020-01560-0 33235291
Attalla, S., Taifour, T., Bui, T. & Muller, W. Insights from transgenic mouse models of PyMT-induced breast cancer: Recapitulating human breast cancer progression in vivo. Oncogene 40, 475–491 (2021).33235291 10.1038/s41388-020-01560-0
175. Pang Y Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation J. Hepatol. 2020 73 1155 1169 10.1016/j.jhep.2020.05.028 32461121
Pang, Y. et al. Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. J. Hepatol. 73, 1155–1169 (2020).32461121 10.1016/j.jhep.2020.05.028
176. Troskie RL Long-read cDNA sequencing identifies functional pseudogenes in the human transcriptome Genome Biol. 2021 22 146 10.1186/s13059-021-02369-0 33971925
Troskie, R. L. et al. Long-read cDNA sequencing identifies functional pseudogenes in the human transcriptome. Genome Biol. 22, 146 (2021).33971925 10.1186/s13059-021-02369-0
177. Dubois ML UBB pseudogene 4 encodes functional ubiquitin variants Nat. Commun. 2020 11 1306 10.1038/s41467-020-15090-6 32161257
Dubois, M. L. et al. UBB pseudogene 4 encodes functional ubiquitin variants. Nat. Commun. 11, 1306 (2020).32161257 10.1038/s41467-020-15090-6
178. Palla AR Reprogramming activity of NANOGP8, a NANOG family member widely expressed in cancer Oncogene 2014 33 2513 2519 10.1038/onc.2013.196 23752184
Palla, A. R. et al. Reprogramming activity of NANOGP8, a NANOG family member widely expressed in cancer. Oncogene 33, 2513–2519 (2014).23752184 10.1038/onc.2013.196
179. Singovski G In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases J. Mol. Cell Biol. 2016 8 157 173 10.1093/jmcb/mjv034 26031752
Singovski, G. et al. In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases. J. Mol. Cell Biol. 8, 157–173 (2016).26031752 10.1093/jmcb/mjv034
180. Jeter CR Functional evidence that the self-renewal gene NANOG regulates human tumor development Stem Cells 2009 27 993 1005 10.1002/stem.29 19415763
Jeter, C. R. et al. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27, 993–1005 (2009).19415763 10.1002/stem.29
181. Jeter CR NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation Oncogene 2011 30 3833 3845 10.1038/onc.2011.114 21499299
Jeter, C. R. et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30, 3833–3845 (2011).21499299 10.1038/onc.2011.114
182. Zhang K Fowler M Glass J Yin H Activated 5′flanking region of NANOGP8 in a self-renewal environment is associated with increased sphere formation and tumor growth of prostate cancer cells Prostate 2014 74 381 394 10.1002/pros.22759 24318967
Zhang, K., Fowler, M., Glass, J. & Yin, H. Activated 5′flanking region of NANOGP8 in a self-renewal environment is associated with increased sphere formation and tumor growth of prostate cancer cells. Prostate 74, 381–394 (2014).24318967 10.1002/pros.22759
183. Uchino K Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells Exp. Cell Res. 2012 318 1799 1807 10.1016/j.yexcr.2012.04.011 22677041
Uchino, K. et al. Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells. Exp. Cell Res. 318, 1799–1807 (2012).22677041 10.1016/j.yexcr.2012.04.011
184. Zhang J NANOG modulates stemness in human colorectal cancer Oncogene 2013 32 4397 4405 10.1038/onc.2012.461 23085761
Zhang, J. et al. NANOG modulates stemness in human colorectal cancer. Oncogene 32, 4397–4405 (2013).23085761 10.1038/onc.2012.461
185. Ma X Wang B Wang X Luo Y Fan W NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells PLoS One 2018 13 e0192436 10.1371/journal.pone.0192436 29689047
Ma, X., Wang, B., Wang, X., Luo, Y. & Fan, W. NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells. PLoS One 13, e0192436 (2018).29689047 10.1371/journal.pone.0192436
186. Kawamura N CRISPR/Cas9-mediated gene knockout of NANOG and NANOGP8 decreases the malignant potential of prostate cancer cells Oncotarget 2015 6 22361 22374 10.18632/oncotarget.4293 26087476
Kawamura, N. et al. CRISPR/Cas9-mediated gene knockout of NANOG and NANOGP8 decreases the malignant potential of prostate cancer cells. Oncotarget 6, 22361–22374 (2015).26087476 10.18632/oncotarget.4293
187. Ishiguro T Differential expression of nanog1 and nanogp8 in colon cancer cells Biochem. Biophys. Res. Commun. 2012 418 199 204 10.1016/j.bbrc.2011.10.123 22079639
Ishiguro, T. et al. Differential expression of nanog1 and nanogp8 in colon cancer cells. Biochem. Biophys. Res. Commun. 418, 199–204 (2012).22079639 10.1016/j.bbrc.2011.10.123
188. Mattoo AR Zhang J Espinoza LA Jessup JM Inhibition of NANOG/NANOGP8 downregulates MCL-1 in colorectal cancer cells and enhances the therapeutic efficacy of BH3 mimetics Clin. Cancer Res. 2014 20 5446 5455 10.1158/1078-0432.CCR-14-1134 25208882
Mattoo, A. R., Zhang, J., Espinoza, L. A. & Jessup, J. M. Inhibition of NANOG/NANOGP8 downregulates MCL-1 in colorectal cancer cells and enhances the therapeutic efficacy of BH3 mimetics. Clin. Cancer Res. 20, 5446–5455 (2014).25208882 10.1158/1078-0432.CCR-14-1134
189. Jiang Z Liu Y Wang C Oncogenic NanogP8 expression regulates cell proliferation and migration through the Akt/mTOR signaling pathway in human gastric cancer — SGC-7901 cell line Onco. Targets Ther. 2016 9 4859 4866 10.2147/OTT.S97861 27563247
Jiang, Z., Liu, Y. & Wang, C. Oncogenic NanogP8 expression regulates cell proliferation and migration through the Akt/mTOR signaling pathway in human gastric cancer — SGC-7901 cell line. Onco. Targets Ther. 9, 4859–4866 (2016).27563247 10.2147/OTT.S97861
190. Li L NANOGP8 expression regulates gastric cancer cell progression by transactivating DBC1 in gastric cancer MKN-45 cells Oncol. Lett. 2019 17 555 563 30655801
Li, L. et al. NANOGP8 expression regulates gastric cancer cell progression by transactivating DBC1 in gastric cancer MKN-45 cells. Oncol. Lett. 17, 555–563 (2019).30655801
191. Jeter CR NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis Cell Discov. 2016 2 16041 10.1038/celldisc.2016.41 27867534
Jeter, C. R. et al. NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis. Cell Discov. 2, 16041 (2016).27867534 10.1038/celldisc.2016.41
192. Liu B Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model Oncotarget 2017 8 52746 52760 10.18632/oncotarget.17186 28881767
Liu, B. et al. Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model. Oncotarget 8, 52746–52760 (2017).28881767 10.18632/oncotarget.17186
193. Badeaux MA In vivo functional studies of tumor-specific retrogene NanogP8 in transgenic animals Cell Cycle 2013 12 2395 2408 10.4161/cc.25402 23839044
Badeaux, M. A. et al. In vivo functional studies of tumor-specific retrogene NanogP8 in transgenic animals. Cell Cycle 12, 2395–2408 (2013).23839044 10.4161/cc.25402
194. Lu X Mazur SJ Lin T Appella E Xu Y The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis Oncogene 2014 33 2655 2664 10.1038/onc.2013.209 23770853
Lu, X., Mazur, S. J., Lin, T., Appella, E. & Xu, Y. The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene 33, 2655–2664 (2014).23770853 10.1038/onc.2013.209
195. Sui Y Roles of NANOGP8 in cancer metastasis and cancer stem cell invasion during development of castration-resistant prostate cancer Ann. Transl. Med. 2021 9 45 45 10.21037/atm-20-1638 33553338
Sui, Y. et al. Roles of NANOGP8 in cancer metastasis and cancer stem cell invasion during development of castration-resistant prostate cancer. Ann. Transl. Med. 9, 45–45 (2021).33553338 10.21037/atm-20-1638
196. Lei M Zheng G Ning Q Zheng J Dong D Translation and functional roles of circular RNAs in human cancer Mol. Cancer 2020 19 30 10.1186/s12943-020-1135-7 32059672
Lei, M., Zheng, G., Ning, Q., Zheng, J. & Dong, D. Translation and functional roles of circular RNAs in human cancer. Mol. Cancer 19, 30 (2020).32059672 10.1186/s12943-020-1135-7
197. Yang Y Extensive translation of circular RNAs driven by N6-methyladenosine Cell Res 2017 27 626 641 10.1038/cr.2017.31 28281539
Yang, Y. et al. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 27, 626–641 (2017).28281539 10.1038/cr.2017.31
198. Shi Y Jia X Xu J The new function of circRNA: translation Clin. Transl. Oncol. 2020 22 2162 2169 10.1007/s12094-020-02371-1 32449127
Shi, Y., Jia, X. & Xu, J. The new function of circRNA: translation. Clin. Transl. Oncol. 22, 2162–2169 (2020).32449127 10.1007/s12094-020-02371-1
199. Wang Y Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas Mol. Cancer 2022 21 13 10.1186/s12943-021-01484-7 34996480
Wang, Y. et al. Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas. Mol. Cancer 21, 13 (2022).34996480 10.1186/s12943-021-01484-7
200. Hansen TB Signal and noise in circRNA translation Methods 2021 196 68 73 10.1016/j.ymeth.2021.02.007 33588029
Hansen, T. B. Signal and noise in circRNA translation. Methods 196, 68–73 (2021).33588029 10.1016/j.ymeth.2021.02.007
201. Mecozzi N Genetic tools for the stable overexpression of circular RNAs RNA Biol. 2022 19 353 363 10.1080/15476286.2022.2043041 35289721
Mecozzi, N. et al. Genetic tools for the stable overexpression of circular RNAs. RNA Biol. 19, 353–363 (2022).35289721 10.1080/15476286.2022.2043041
202. Kong S Tao M Shen X Ju S Translatable circRNAs and lncRNAs: Driving mechanisms and functions of their translation products Cancer Lett. 2020 483 59 65 10.1016/j.canlet.2020.04.006 32360179
Kong, S., Tao, M., Shen, X. & Ju, S. Translatable circRNAs and lncRNAs: Driving mechanisms and functions of their translation products. Cancer Lett. 483, 59–65 (2020).32360179 10.1016/j.canlet.2020.04.006
203. Sinha T Panigrahi C Das D Chandra Panda A Circular RNA translation, a path to hidden proteome Wiley Interdiscip. Rev. RNA 2022 13 e1685 10.1002/wrna.1685 34342387
Sinha, T., Panigrahi, C., Das, D. & Chandra Panda, A. Circular RNA translation, a path to hidden proteome. Wiley Interdiscip. Rev. RNA 13, e1685 (2022).34342387 10.1002/wrna.1685
204. Zhang L Gao H Li X Yu F Li P The important regulatory roles of circRNA-encoded proteins or peptides in cancer pathogenesis (review) Int. J. Oncol. 2023 64 19 10.3892/ijo.2023.5607
Zhang, L., Gao, H., Li, X., Yu, F. & Li, P. The important regulatory roles of circRNA-encoded proteins or peptides in cancer pathogenesis (review). Int. J. Oncol. 64, 19 (2023).10.3892/ijo.2023.5607
205. He Y Targeting PI3K/Akt signal transduction for cancer therapy Signal Transduct. Target. Ther. 2021 6 425 10.1038/s41392-021-00828-5 34916492
He, Y. et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct. Target. Ther. 6, 425 (2021).34916492 10.1038/s41392-021-00828-5
206. Lan H Sun Y FBXW7 E3 ubiquitin ligase: Degrading, not degrading, or being degraded Protein Cell 2019 10 861 863 10.1007/s13238-019-0652-x 31342282
Lan, H. & Sun, Y. FBXW7 E3 ubiquitin ligase: Degrading, not degrading, or being degraded. Protein Cell 10, 861–863 (2019).31342282 10.1007/s13238-019-0652-x
207. Yang Y Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis J. Natl. Cancer Inst. 2018 110 304 315 10.1093/jnci/djx166 28903484
Yang, Y. et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J. Natl. Cancer Inst. 110, 304–315 (2018).28903484 10.1093/jnci/djx166
208. Marín-Béjar O Pint lincRNA connects the p53 pathway with epigenetic silencing by the polycomb repressive complex 2 Genome Biol. 2013 14 R104 10.1186/gb-2013-14-9-r104 24070194
Marín-Béjar, O. et al. Pint lincRNA connects the p53 pathway with epigenetic silencing by the polycomb repressive complex 2. Genome Biol. 14, R104 (2013).24070194 10.1186/gb-2013-14-9-r104
209. Zhang M A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma Nat. Commun. 2018 9 4475 10.1038/s41467-018-06862-2 30367041
Zhang, M. et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat. Commun. 9, 4475 (2018).30367041 10.1038/s41467-018-06862-2
210. Matsumoto A MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide Nature 2017 541 228 232 10.1038/nature21034 28024296
Matsumoto, A. et al. MTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541, 228–232 (2017).28024296 10.1038/nature21034
211. Honkala A Malhotra SV Kummar S Junttila MR Harnessing the predictive power of preclinical models for oncology drug development Nat. Rev. Drug Discov. 2022 21 99 114 10.1038/s41573-021-00301-6 34702990
Honkala, A., Malhotra, S. V., Kummar, S. & Junttila, M. R. Harnessing the predictive power of preclinical models for oncology drug development. Nat. Rev. Drug Discov. 21, 99–114 (2022).34702990 10.1038/s41573-021-00301-6
212. Winkle M El-Daly SM Fabbri M Calin GA Noncoding RNA therapeutics—challenges and potential solutions Nat. Rev. Drug Discov. 2021 20 629 651 10.1038/s41573-021-00219-z 34145432
Winkle, M., El-Daly, S. M., Fabbri, M. & Calin, G. A. Noncoding RNA therapeutics—challenges and potential solutions. Nat. Rev. Drug Discov. 20, 629–651 (2021).34145432 10.1038/s41573-021-00219-z
213. Zhu Y Zhu L Wang X Jin H RNA-based therapeutics: an overview and prospectus Cell Death Dis. 2022 13 644 10.1038/s41419-022-05075-2 35871216
Zhu, Y., Zhu, L., Wang, X. & Jin, H. RNA-based therapeutics: an overview and prospectus. Cell Death Dis. 13, 644 (2022).35871216 10.1038/s41419-022-05075-2
214. Liu K AEG-1 3′-untranslated region functions as a ceRNA in inducing epithelial-mesenchymal transition of human non-small cell lung cancer by regulating miR-30a activity Eur. J. Cell Biol. 2015 94 22 31 10.1016/j.ejcb.2014.10.006 25484183
Liu, K. et al. AEG-1 3′-untranslated region functions as a ceRNA in inducing epithelial-mesenchymal transition of human non-small cell lung cancer by regulating miR-30a activity. Eur. J. Cell Biol. 94, 22–31 (2015).25484183 10.1016/j.ejcb.2014.10.006
215. Qian M BCL11B regulates MICA/B-mediated immune response by acting as a competitive endogenous RNA Oncogene 2020 39 1514 1526 10.1038/s41388-019-1083-0 31673069
Qian, M. et al. BCL11B regulates MICA/B-mediated immune response by acting as a competitive endogenous RNA. Oncogene 39, 1514–1526 (2020).31673069 10.1038/s41388-019-1083-0
216. Hu J The CCR2 3′UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis J. Cell Sci. 2017 130 3399 3413 10.1242/jcs.202127 28818997
Hu, J. et al. The CCR2 3′UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis. J. Cell Sci. 130, 3399–3413 (2017).28818997 10.1242/jcs.202127
217. Rutnam ZJ Yang BB The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions J. Cell Sci. 2012 125 2075 2085 10.1242/jcs.100818 22637644
Rutnam, Z. J. & Yang, B. B. The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions. J. Cell Sci. 125, 2075–2085 (2012).22637644 10.1242/jcs.100818
218. Jeyapalan Z Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis Nucleic Acids Res 2011 39 3026 3041 10.1093/nar/gkq1003 21149267
Jeyapalan, Z. et al. Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis. Nucleic Acids Res. 39, 3026–3041 (2011).21149267 10.1093/nar/gkq1003
219. Weng J CD44 3′-untranslated region functions as a competing endogenous RNA to enhance NK sensitivity of liver cancer stem cell by regulating ULBP2 expression Int. J. Biol. Sci. 2019 15 1664 1675 10.7150/ijbs.35216 31360109
Weng, J. et al. CD44 3′-untranslated region functions as a competing endogenous RNA to enhance NK sensitivity of liver cancer stem cell by regulating ULBP2 expression. Int. J. Biol. Sci. 15, 1664–1675 (2019).31360109 10.7150/ijbs.35216
220. Li X STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer Oncotarget 2016 7 23197 23211 10.18632/oncotarget.8099 26985770
Li, X. et al. STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer. Oncotarget 7, 23197–23211 (2016).26985770 10.18632/oncotarget.8099
221. Chen PC c-Myc acts as a competing endogenous RNA to sponge miR-34a, in the upregulation of CD44, in urothelial carcinoma Cancers 2019 11 1457 10.3390/cancers11101457 31569404
Chen, P. C. et al. c-Myc acts as a competing endogenous RNA to sponge miR-34a, in the upregulation of CD44, in urothelial carcinoma. Cancers 11, 1457 (2019).31569404 10.3390/cancers11101457
222. Wang B CYP4Z1 3′UTR represses migration of human breast cancer cells Biochem. Biophys. Res. Commun. 2016 478 900 907 10.1016/j.bbrc.2016.08.048 27520371
Wang, B. et al. CYP4Z1 3′UTR represses migration of human breast cancer cells. Biochem. Biophys. Res. Commun. 478, 900–907 (2016).27520371 10.1016/j.bbrc.2016.08.048
223. Zheng L Li X Gu Y Lv X Xi T Correction to: The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1 Breast Cancer Res. Treat. 2020 179 521 522 10.1007/s10549-019-05478-4 31655919
Zheng, L., Li, X., Gu, Y., Lv, X. & Xi, T. Correction to: The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1. Breast Cancer Res. Treat. 179, 521–522 (2020).31655919 10.1007/s10549-019-05478-4
224. Zheng L Li X Gu Y Lv X Xi T The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1 Breast Cancer Res. Treat. 2015 150 105 118 10.1007/s10549-015-3298-2 25701119
Zheng, L., Li, X., Gu, Y., Lv, X. & Xi, T. The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1. Breast Cancer Res. Treat. 150, 105–118 (2015).25701119 10.1007/s10549-015-3298-2
225. Cheng FHC E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness Cancer Sci. 2019 110 1085 1095 10.1111/cas.13920 30582655
Cheng, F. H. C. et al. E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness. Cancer Sci. 110, 1085–1095 (2019).30582655 10.1111/cas.13920
226. Yang J FOXO1 3′UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity FEBS Lett. 2014 588 3218 3224 10.1016/j.febslet.2014.07.003 25017439
Yang, J. et al. FOXO1 3′UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity. FEBS Lett. 588, 3218–3224 (2014).25017439 10.1016/j.febslet.2014.07.003
227. Yang ZP Ma HS Wang SS Wang L Liu T LAMC1 mRNA promotes malignancy of hepatocellular carcinoma cells by competing for MicroRNA-124 binding with CD151 IUBMB Life 2017 69 595 605 10.1002/iub.1642 28524360
Yang, Z. P., Ma, H. S., Wang, S. S., Wang, L. & Liu, T. LAMC1 mRNA promotes malignancy of hepatocellular carcinoma cells by competing for MicroRNA-124 binding with CD151. IUBMB Life 69, 595–605 (2017).28524360 10.1002/iub.1642
228. Wang C Mao C Lai Y Cai Z Chen W MMP1 3′UTR facilitates the proliferation and migration of human oral squamous cell carcinoma by sponging miR-188-5p to up-regulate SOX4 and CDK4 Mol. Cell Biochem. 2021 476 785 796 10.1007/s11010-020-03944-y 33090337
Wang, C., Mao, C., Lai, Y., Cai, Z. & Chen, W. MMP1 3′UTR facilitates the proliferation and migration of human oral squamous cell carcinoma by sponging miR-188-5p to up-regulate SOX4 and CDK4. Mol. Cell Biochem. 476, 785–796 (2021).33090337 10.1007/s11010-020-03944-y
229. Li J Pecanex functions as a competitive endogenous RNA of S-phase kinase associated protein 2 in lung cancer Cancer Lett. 2017 406 36 46 10.1016/j.canlet.2017.07.030 28789966
Li, J. et al. Pecanex functions as a competitive endogenous RNA of S-phase kinase associated protein 2 in lung cancer. Cancer Lett. 406, 36–46 (2017).28789966 10.1016/j.canlet.2017.07.030
230. Huang X PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a J. Exp. Clin. Cancer Res. 2017 36 129 10.1186/s13046-017-0593-2 28915924
Huang, X. et al. PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a. J. Exp. Clin. Cancer Res. 36, 129 (2017).28915924 10.1186/s13046-017-0593-2
231. Liu T PIK3C2A mRNA functions as a miR-124 sponge to facilitate CD151 expression and enhance malignancy of hepatocellular carcinoma cells Oncotarget 2016 7 43376 43389 10.18632/oncotarget.9716 27270320
Liu, T. et al. PIK3C2A mRNA functions as a miR-124 sponge to facilitate CD151 expression and enhance malignancy of hepatocellular carcinoma cells. Oncotarget 7, 43376–43389 (2016).27270320 10.18632/oncotarget.9716
232. Wan X Co-expression analysis revealed PTCH1-3′UTR promoted cell migration and invasion by activating miR-101-3p/SLC39A6 axis in non-small cell lung cancer: implicating the novel function of PTCH1 Oncotarget 2018 9 4798 4813 10.18632/oncotarget.23219 29435142
Wan, X. et al. Co-expression analysis revealed PTCH1-3′UTR promoted cell migration and invasion by activating miR-101-3p/SLC39A6 axis in non-small cell lung cancer: implicating the novel function of PTCH1. Oncotarget 9, 4798–4813 (2018).29435142 10.18632/oncotarget.23219
233. Li J Yu H Xi M Ma D Lu X The SNAI1 3′UTR functions as a sponge for multiple migration-/invasion-related microRNAs Tumour Biol. 2015 36 1067 1072 10.1007/s13277-014-2733-z 25326810
Li, J., Yu, H., Xi, M., Ma, D. & Lu, X. The SNAI1 3′UTR functions as a sponge for multiple migration-/invasion-related microRNAs. Tumour Biol. 36, 1067–1072 (2015).25326810 10.1007/s13277-014-2733-z
234. Li J Wang J Yue H Lu X SNAI2 3′untranslated region promotes the invasion of ovarian cancer cells by inducing MARCKS expression J. Cancer 2019 10 2480 2487 10.7150/jca.29489 31258754
Li, J., Wang, J., Yue, H. & Lu, X. SNAI2 3′untranslated region promotes the invasion of ovarian cancer cells by inducing MARCKS expression. J. Cancer 10, 2480–2487 (2019).31258754 10.7150/jca.29489
235. Zheng L StarD13 3′-untranslated region functions as a ceRNA for TP53INP1 in prohibiting migration and invasion of breast cancer cells by regulating miR-125b activity Eur. J. Cell Biol. 2018 97 23 31 10.1016/j.ejcb.2017.11.002 29146309
Zheng, L. et al. StarD13 3′-untranslated region functions as a ceRNA for TP53INP1 in prohibiting migration and invasion of breast cancer cells by regulating miR-125b activity. Eur. J. Cell Biol. 97, 23–31 (2018).29146309 10.1016/j.ejcb.2017.11.002
236. Guo X Displacement of Bax by BMF mediates STARD13 3′UTR-induced breast cancer cells apoptosis in an miRNA-depedent manner Mol. Pharm. 2018 15 63 71 10.1021/acs.molpharmaceut.7b00727 29179557
Guo, X. et al. Displacement of Bax by BMF mediates STARD13 3′UTR-induced breast cancer cells apoptosis in an miRNA-depedent manner. Mol. Pharm. 15, 63–71 (2018).29179557 10.1021/acs.molpharmaceut.7b00727
237. Zheng L STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling J. Hematol. Oncol. 2018 11 72 10.1186/s13045-018-0613-5 29848346
Zheng, L. et al. STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling. J. Hematol. Oncol. 11, 72 (2018).29848346 10.1186/s13045-018-0613-5
238. Zhang H Wang F Hu Y STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas Biotechnol. Lett. 2017 39 207 217 10.1007/s10529-016-2253-6 27844181
Zhang, H., Wang, F. & Hu, Y. STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas. Biotechnol. Lett. 39, 207–217 (2017).27844181 10.1007/s10529-016-2253-6
239. Wang Z Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer Sci. Rep. 2017 7 4281 10.1038/s41598-017-04368-3 28655924
Wang, Z. et al. Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer. Sci. Rep. 7, 4281 (2017).28655924 10.1038/s41598-017-04368-3
240. Fang L Versican 3′-untranslated region (3′-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity FASEB J. 2013 27 907 919 10.1096/fj.12-220905 23180826
Fang, L. et al. Versican 3′-untranslated region (3′-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. FASEB J. 27, 907–919 (2013).23180826 10.1096/fj.12-220905
241. Wu Q XIAP 3′-untranslated region as a ceRNA promotes FSCN1 function in inducing the progression of breast cancer by binding endogenous miR-29a-5p Oncotarget 2017 8 16784 16800 10.18632/oncotarget.15159 28186968
Wu, Q. et al. XIAP 3′-untranslated region as a ceRNA promotes FSCN1 function in inducing the progression of breast cancer by binding endogenous miR-29a-5p. Oncotarget 8, 16784–16800 (2017).28186968 10.18632/oncotarget.15159
242. Wu WY Tao SQ Wang XN Lobie PE Wu ZS XIAP 3′-untranslated region serves as a competitor for HMGA2 by arresting endogenous let-7a-5p in human hepatocellular carcinoma Tumour Biol. 2017 39 1010428317719578 10.1177/1010428317719578 28691642
Wu, W. Y., Tao, S. Q., Wang, X. N., Lobie, P. E. & Wu, Z. S. XIAP 3′-untranslated region serves as a competitor for HMGA2 by arresting endogenous let-7a-5p in human hepatocellular carcinoma. Tumour Biol. 39, 1010428317719578 (2017).28691642 10.1177/1010428317719578
243. Zhu S An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis Nat. Commun. 2020 11 1685 10.1038/s41467-020-15403-9 32245947
Zhu, S. et al. An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis. Nat. Commun. 11, 1685 (2020).32245947 10.1038/s41467-020-15403-9
244. Wu S A novel micropeptide encoded by Y-linked LINC00278 links cigarette smoking and AR signaling in male esophageal squamous cell carcinoma Cancer Res 2020 80 2790 2803 10.1158/0008-5472.CAN-19-3440 32169859
Wu, S. et al. A novel micropeptide encoded by Y-linked LINC00278 links cigarette smoking and AR signaling in male esophageal squamous cell carcinoma. Cancer Res. 80, 2790–2803 (2020).32169859 10.1158/0008-5472.CAN-19-3440
245. Li XL A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells Elife 2020 9 e53734 10.7554/eLife.53734 33112233
Li, X. L. et al. A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells. Elife 9, e53734 (2020).33112233 10.7554/eLife.53734
246. Wang Y LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis J. Exp. Med. 2020 217 jem.20190950 10.1084/jem.20190950 31816634
Wang, Y. et al. LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis. J. Exp. Med. 217, jem.20190950 (2020).31816634 10.1084/jem.20190950
247. Zou M Oncogenic activation of MAP kinase by BRAF pseudogene in thyroid tumors Neoplasia 2009 11 57 65 10.1593/neo.81044 19107232
Zou, M. et al. Oncogenic activation of MAP kinase by BRAF pseudogene in thyroid tumors. Neoplasia 11, 57–65 (2009).19107232 10.1593/neo.81044
248. Sun C CRIPTO3, a presumed pseudogene, is expressed in cancer Biochem. Biophys. Res. Commun. 2008 377 215 220 10.1016/j.bbrc.2008.09.113 18835250
Sun, C. et al. CRIPTO3, a presumed pseudogene, is expressed in cancer. Biochem. Biophys. Res. Commun. 377, 215–220 (2008).18835250 10.1016/j.bbrc.2008.09.113
249. Zhang M Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development Commun. Biol. 2023 6 1059 10.1038/s42003-023-05438-1 37853052
Zhang, M. et al. Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development. Commun. Biol. 6, 1059 (2023).37853052 10.1038/s42003-023-05438-1
250. Moreau-Aubry A A processed pseudogene codes for a new antigen recognized by a CD8(+) T cell clone on melanoma J. Exp. Med. 2000 191 1617 1624 10.1084/jem.191.9.1617 10790436
Moreau-Aubry, A. et al. A processed pseudogene codes for a new antigen recognized by a CD8(+) T cell clone on melanoma. J. Exp. Med. 191, 1617–1624 (2000).10790436 10.1084/jem.191.9.1617
251. Lettnin AP Silencing the OCT4-PG1 pseudogene reduces OCT-4 protein levels and changes characteristics of the multidrug resistance phenotype in chronic myeloid leukemia Mol. Biol. Rep. 2019 46 1873 1884 10.1007/s11033-019-04639-4 30721421
Lettnin, A. P. et al. Silencing the OCT4-PG1 pseudogene reduces OCT-4 protein levels and changes characteristics of the multidrug resistance phenotype in chronic myeloid leukemia. Mol. Biol. Rep. 46, 1873–1884 (2019).30721421 10.1007/s11033-019-04639-4
252. Li T A novel peptide P1-121aa encoded by STK24P1 regulates vasculogenic mimicry via ELF2 phosphorylation in glioblastoma Exp. Neurol. 2023 367 114477 10.1016/j.expneurol.2023.114477 37406957
Li, T. et al. A novel peptide P1-121aa encoded by STK24P1 regulates vasculogenic mimicry via ELF2 phosphorylation in glioblastoma. Exp. Neurol. 367, 114477 (2023).37406957 10.1016/j.expneurol.2023.114477
253. Wang T A novel protein encoded by circASK1 ameliorates gefitinib resistance in lung adenocarcinoma by competitively activating ASK1-dependent apoptosis Cancer Lett. 2021 520 321 331 10.1016/j.canlet.2021.08.007 34389432
Wang, T. et al. A novel protein encoded by circASK1 ameliorates gefitinib resistance in lung adenocarcinoma by competitively activating ASK1-dependent apoptosis. Cancer Lett. 520, 321–331 (2021).34389432 10.1016/j.canlet.2021.08.007
254. Peng Y A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression Mol. Cancer 2021 20 158 10.1186/s12943-021-01457-w 34863211
Peng, Y. et al. A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression. Mol. Cancer 20, 158 (2021).34863211 10.1186/s12943-021-01457-w
255. Zhao W Zhang Y Zhu Y Circular RNA circβ-catenin aggravates the malignant phenotype of non-small-cell lung cancer via encoding a peptide J. Clin. Lab. Anal. 2021 35 e23900 10.1002/jcla.23900 34296778
Zhao, W., Zhang, Y. & Zhu, Y. Circular RNA circβ-catenin aggravates the malignant phenotype of non-small-cell lung cancer via encoding a peptide. J. Clin. Lab. Anal. 35, e23900 (2021).34296778 10.1002/jcla.23900
256. Liang WC Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway Genome Biol. 2019 20 84 10.1186/s13059-019-1685-4 31027518
Liang, W. C. et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 20, 84 (2019).31027518 10.1186/s13059-019-1685-4
257. Gu C CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma Mol. Cancer 2021 20 84 10.1186/s12943-021-01380-0 34090465
Gu, C. et al. CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma. Mol. Cancer 20, 84 (2021).34090465 10.1186/s12943-021-01380-0
258. Zhang Y CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability Mol. Cancer 2021 20 101 10.1186/s12943-021-01390-y 34384442
Zhang, Y. et al. CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability. Mol. Cancer 20, 101 (2021).34384442 10.1186/s12943-021-01390-y
259. Gao X Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling Nat. Cell Biol. 2021 23 278 291 10.1038/s41556-021-00639-4 33664496
Gao, X. et al. Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling. Nat. Cell Biol. 23, 278–291 (2021).33664496 10.1038/s41556-021-00639-4
260. Li Y circ-EIF6 encodes EIF6-224aa to promote TNBC progression via stabilizing MYH9 and activating the Wnt/beta-catenin pathway Mol. Ther. 2022 30 415 430 10.1016/j.ymthe.2021.08.026 34450253
Li, Y. et al. circ-EIF6 encodes EIF6-224aa to promote TNBC progression via stabilizing MYH9 and activating the Wnt/beta-catenin pathway. Mol. Ther. 30, 415–430 (2022).34450253 10.1016/j.ymthe.2021.08.026
261. Chen C-K Structured elements drive extensive circular RNA translation Mol. Cell 2021 81 4300 4318.e13 10.1016/j.molcel.2021.07.042 34437836
Chen, C.-K. et al. Structured elements drive extensive circular RNA translation. Mol. Cell 81, 4300–4318.e13 (2021).34437836 10.1016/j.molcel.2021.07.042
262. Pan Z A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer Mol. Cancer 2020 19 71 10.1186/s12943-020-01179-5 32241279
Pan, Z. et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol. Cancer 19, 71 (2020).32241279 10.1186/s12943-020-01179-5
263. Gu C circGprc5a promoted bladder oncogenesis and metastasis through Gprc5a-targeting peptide Mol. Ther. Nucleic Acids 2018 13 633 641 10.1016/j.omtn.2018.10.008 30497053
Gu, C. et al. circGprc5a promoted bladder oncogenesis and metastasis through Gprc5a-targeting peptide. Mol. Ther. Nucleic Acids 13, 633–641 (2018).30497053 10.1016/j.omtn.2018.10.008
264. Song J A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5 J. Exp. Clin. Cancer Res. 2022 41 171 10.1186/s13046-022-02374-6 35538499
Song, J. et al. A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5. J. Exp. Clin. Cancer Res. 41, 171 (2022).35538499 10.1186/s13046-022-02374-6
265. Li J Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab Mol. Cancer 2020 19 142 10.1186/s12943-020-01259-6 32917240
Li, J. et al. Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab. Mol. Cancer 19, 142 (2020).32917240 10.1186/s12943-020-01259-6
266. Jiang T A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling Mol. Cancer 2021 20 66 10.1186/s12943-021-01358-y 33836754
Jiang, T. et al. A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling. Mol. Cancer 20, 66 (2021).33836754 10.1186/s12943-021-01358-y
267. Wang L A novel tumour suppressor protein encoded by circMAPK14 inhibits progression and metastasis of colorectal cancer by competitively binding to MKK6 Clin. Transl. Med. 2021 11 e613 10.1002/ctm2.613 34709743
Wang, L. et al. A novel tumour suppressor protein encoded by circMAPK14 inhibits progression and metastasis of colorectal cancer by competitively binding to MKK6. Clin. Transl. Med. 11, e613 (2021).34709743 10.1002/ctm2.613
268. Duan JL A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma Mol. Cancer 2022 21 93 10.1186/s12943-022-01537-5 35366894
Duan, J. L. et al. A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma. Mol. Cancer 21, 93 (2022).35366894 10.1186/s12943-022-01537-5
269. Liang ZX A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation Mol. Cancer 2021 20 103 10.1186/s12943-021-01404-9 34412652
Liang, Z. X. et al. A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation. Mol. Cancer 20, 103 (2021).34412652 10.1186/s12943-021-01404-9
270. Zheng X A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling Mol. Cancer 2019 18 47 10.1186/s12943-019-1010-6 30925892
Zheng, X. et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol. Cancer 18, 47 (2019).30925892 10.1186/s12943-019-1010-6
271. Zhang M A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis Oncogene 2018 37 1805 1814 10.1038/s41388-017-0019-9 29343848
Zhang, M. et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 37, 1805–1814 (2018).29343848 10.1038/s41388-017-0019-9
272. Wu X A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity Genome Biol. 2021 22 33 10.1186/s13059-020-02250-6 33446260
Wu, X. et al. A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity. Genome Biol. 22, 33 (2021).33446260 10.1186/s13059-020-02250-6
273. Lyu Y A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling Cell Death Dis. 2023 14 346 10.1038/s41419-023-05865-2 37264022
Lyu, Y. et al. A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling. Cell Death Dis. 14, 346 (2023).37264022 10.1038/s41419-023-05865-2
274. Li F A peptide CORO1C-47aa encoded by the circular noncoding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis J. Biol. Chem. 2021 297 101182 10.1016/j.jbc.2021.101182 34534547
Li, F. et al. A peptide CORO1C-47aa encoded by the circular noncoding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis. J. Biol. Chem. 297, 101182 (2021).34534547 10.1016/j.jbc.2021.101182
275. Yang F p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation Mol. Cancer 2021 20 123 10.1186/s12943-021-01421-8 34579723
Yang, F. et al. p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation. Mol. Cancer 20, 123 (2021).34579723 10.1186/s12943-021-01421-8
