
==== Front
Oncol Rep
Oncol Rep
Oncology Reports
1021-335X
1791-2431
D.A. Spandidos

39219266
10.3892/or.2024.8801
OR-52-5-08801
Review
The role of lncRNA binding to RNA‑binding proteins to regulate mRNA stability in cancer progression and drug resistance mechanisms (Review)
Zhang Nianjie
Wen Kunming
Department of Gastrointestinal Surgery, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523059, P.R. China
Correspondence to: Professor Kunming Wen, Department of Gastrointestinal Surgery, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Xinguyong-wandao Road, Wanjiang Street, Dongguan, Guangdong 523059, P.R. China, E-mail: 381224619@qq.com
11 2024
23 8 2024
23 8 2024
52 5 14227 4 2024
13 8 2024
Copyright: © 2024 Zhang and Wen.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Cancer is a disease that poses a serious threat to human health, the occurrence and development of which involves complex molecular mechanisms. Long non-coding RNAs (lncRNAs) and RNA-binding proteins (RBPs) are important regulatory molecules within cells, which have garnered extensive attention in cancer research in recent years. The binding of lncRNAs and RBPs plays a crucial role in the post-transcriptional regulation of mRNA, affecting the synthesis of proteins related to cancer by regulating the stability of mRNA. This, in turn, regulates the malignant biological behaviors of tumor cells, such as proliferation and metastasis, and serves an important role in therapeutic resistance. The present study reviewed the role of lncRNA-RBP interactions in the regulation of mRNA stability in various malignant tumors, with a focus on the molecular mechanisms underlying this regulatory interaction. The aim of the present review was to gain a deeper understanding of these molecular mechanisms to provide new strategies and insights for the precise treatment of cancer.

cancer
long non-coding RNA
RNA-binding protein
mRNA stability
regulation
Guizhou Science and Technology Planning ProjectQiankehe Basics-ZK(2024)general 302 Qiankehe Basics-ZK(2022)general 631 The present review was supported by the Guizhou Science and Technology Planning Project [grant nos. Qiankehe Basics-ZK(2024)general 302 and Qiankehe Basics-ZK(2022)general 631].
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pmc1. Introduction

Cancer is a complex disease involving multiple aspects at the genetic, molecular and cellular levels, which is characterized by unlimited cell proliferation, invasion and metastasis (1–3). With global population aging and lifestyle changes, the incidence and mortality rates of cancer are continuously rising, posing significant challenges to the global public health system (4–7). The complexity of cancer treatment lies in its high heterogeneity and adaptability to therapies, and even the most advanced treatments face issues of resistance and relapse (8–10). Therefore, understanding and studying the fundamental biological characteristics and pathogenesis of cancer is crucial for developing new therapeutic strategies.

mRNA is a single-stranded ribonucleic acid transcribed from DNA. Its function is to transfer genetic information from DNA in the nucleus to ribosomes in the cytoplasm, directing the synthesis of proteins to execute various functions. This process is influenced by numerous factors, and the stability of mRNA can ultimately affect its protein expression levels, thereby impacting its functional performance (11). The stability of mRNA is related to the integrity of its structure, which includes the 5′ cap, the 5′ untranslated region (UTR), the open reading frame, the 3′ UTR and the polyadenylated tail [Poly(A) tail] at the 3′ end (12,13). The 5′ cap and Poly(A) tail are crucial for maintaining mRNA stability. When the 5′ cap and Poly(A) tail are present, mRNA is protected from degradation by exonucleases and can continue to be translated into proteins. However, when they are removed, mRNA is degraded by exonucleases, leading to a reduction in the synthesis of its encoded protein products (14,15). Some proteins bind to the 5′ UTR or 3′ UTR of mRNA and can maintain or remove the 5′ cap and Poly(A) tail, thereby affecting whether the mRNA is degraded; this is a key mechanism for regulating mRNA stability.

RNA-binding proteins (RBPs) are important regulatory molecules within cells that bind to RNA to regulate its splicing, transport, translation and degradation, thereby maintaining normal cellular physiological functions (16–18). Studies have found that RBPs can influence mRNA stability through post-transcriptional regulation, playing a regulatory role in the occurrence, development and therapeutic resistance of malignant tumors (19,20). In addition to binding to mRNA, RBPs can bind to long non-coding RNA (lncRNA). lncRNAs are RNA molecules longer than 200 nucleotides that do not encode proteins; however, they maintain normal cellular functions and homeostasis by regulating gene expression, participating in chromatin remodeling, and modulating RNA splicing and translation (21–23). Abnormal expression of lncRNAs and RBPs can significantly affect the biological behavior of cancer (24,25). Studies have found that lncRNAs regulate mRNA stability through interactions with RBPs, which is an important mechanism in cancer progression and drug resistance (26–28).

For the present review, a systematic literature search was conducted using the PubMed platform (https://pubmed.ncbi.nlm.nih.gov/) with key words including ‘lncRNA’, ‘RBP’, ‘mRNA’, ‘RNA stability’, ‘RNA degradation’ and ‘cancer’. Subsequently, articles on how lncRNAs regulate mRNA stability in cancer through interactions with RBPs were screened and analyzed. The present study focused on reviewing the impact of lncRNA-RBP interactions on mRNA stability in cancer, and their roles in cancer occurrence, development and drug resistance, exploring the potential of targeting this mechanism as a new therapeutic strategy for cancer.

2. lncRNA acts as a molecular scaffold, promoting the binding of RBPs to mRNA, thereby regulating mRNA stability

Molecular scaffolds refer to RNA, proteins or other macromolecules that, during normal cellular physiological processes and signal transduction, provide binding sites and interact with multiple molecules. This promotes interactions among these molecules, ensuring appropriate transmission of signals by kinases, receptors and other signaling molecules, thus fulfilling biological functions (29–31). Molecular scaffolds not only speed up the transmission and efficiency of signals but also ensure that signals are accurately transmitted to specific cellular locations, finely regulating cell proliferation, differentiation, metabolism and other important functions (32,33). In cancer, some lncRNAs also act as molecular scaffolds, promoting the binding of RBPs to mRNA, enhancing or weakening mRNA stability, and regulating the synthesis of related proteins (Fig. 1A); this ultimately affects the malignant biological behavior of tumors and therapeutic resistance (34–37).

Enhanced mRNA stability

lncRNA acts as a molecular scaffold to promote the binding of RBPs to the 5′ UTR or 3′ UTR of mRNA, further regulating mRNA stability (38–40). The regulatory effect depends on the function of the RBP. When the RBP stabilizes the 5′ cap or Poly(A) tail of mRNA, it can prevent mRNA from being degraded by exonucleases, enhancing mRNA stability, increasing the synthesis of its encoded protein and thus its corresponding biological functions.

As a molecular scaffold, lncRNA promotes the binding of RBPs to the mRNA of oncogenes or tumor suppressor genes, enhancing their stability and exerting oncogenic or tumor-suppressing effects. Wang et al (41) reported that the lncRNA EGFR-AS1 was highly expressed in renal cancer. After EGFR-AS1 binds with HuR, it promotes the binding of human antigen R (HuR) to the ARE sequence in the 3′ UTR of EGFR mRNA, forming a stable complex that maintains the stability of the Poly(A) tail at the 3′ end of EGFR mRNA, preventing its degradation by exonucleases, thereby increasing its stability. This, in turn, increases EGFR protein synthesis, promoting renal cancer cell proliferation (41). In a study by Wu et al (42), the lncRNA small nucleolar RNA host gene 12 was shown to recruit insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and promote its binding to the 3′ UTR of catenin beta 1 (CTNNB1) mRNA, forming a complex that prevents CTNNB1 mRNA degradation and increases CTNNB1 protein synthesis. The CTNNB1 protein further activates the Wnt/β-catenin signaling pathway, promoting the invasion and metastasis of esophageal cancer (42). Chen et al (43) demonstrated that LINC00659 was lowly expressed in hepatocellular carcinoma (HCC), and its overexpression significantly inhibited HCC proliferation and metastasis. Mechanistic studies have indicated that LINC00659 acts as a molecular scaffold to promote the binding of FUS to SLC10A1 mRNA, preventing its degradation and increasing SLC10A1 protein synthesis. The SLC10A1 protein can block aerobic glycolysis in liver cancer cells, thereby significantly inhibiting HCC proliferation and metastasis (43). Similar mechanisms have also been observed in numerous other types of cancer (Table I) (44–55).

The regulation of mRNA stability by lncRNA as a molecular scaffold promoting RBP binding to mRNA not only influences the malignant biological behavior of cancer, but also plays a role in regulating cancer treatment resistance (56). Ferroptosis is closely related to cancer drug resistance. Unlike classical forms of cell death, such as apoptosis, necrosis or autophagy, ferroptosis is a form of cell death induced by iron-catalyzed lipid peroxidation, primarily involving the peroxidative damage of polyunsaturated fatty acids in cell membranes. Excess iron ions promote the generation of reactive oxygen species (ROS), disrupt cell membrane integrity, lead to cellular dysfunction and ultimately trigger cell death (57–59). Studies have shown that cancer cells develop drug resistance by evading ferroptosis (60–62), while inducing ferroptosis in cancer cells can reverse their drug resistance (63,64). Temozolomide (TMZ) is a primary drug for the treatment of glioma; however, drug resistance is a major challenge in its treatment. Luo et al (65) found that the lncRNA ataxin-8 opposite strand (ATXN8OS) was lowly expressed in glioma, and overexpression of ATXN8OS could inhibit glioma resistance to TMZ. Mechanistic studies indicated that ATXN8OS recruits adenosine deaminase acting on RNA and promotes its binding to glutaminase 2 (GLS2) mRNA, enhancing GLS2 mRNA stability and increasing intracellular GLS2 protein synthesis. GLS2 increases iron ion and ROS levels, promoting ferroptosis in glioma, ultimately enhancing the sensitivity of glioma to TMZ (65).

Decreased mRNA stability

When lncRNA functions as a molecular scaffold to bind RBPs that remove the 5′ cap or Poly(A) tail of mRNA, it leads to mRNA degradation, reducing its stability and the synthesis of its encoded protein, thereby exerting oncogenic or tumor-suppressive effects.

Staufen (STAU)-mediated mRNA decay (SMD) is a post-transcriptional regulatory mechanism of gene expression, which involves the role of STAU in recognizing and promoting the degradation of specific mRNA molecules (66,67). Lu et al (68) found that in breast cancer, the lncRNA TINCR could act as a molecular scaffold to bind STAU1, a member of the Staufen protein family, thus promoting the degradation of oligoadenylate synthetase 1 (OAS1) mRNA through the SMD pathway. Mechanistically, STAU1 binds to the 3′ UTR region of OAS1 mRNA and removes its Poly(A) tail at the 3′ end, ultimately leading to degradation by exonucleases and reducing OAS1 mRNA stability. OAS1 is a tumor suppressor gene, and reduced protein synthesis of OAS1 can promote breast cancer cell proliferation and metastasis (68). Similarly, in ovarian cancer, the lncRNA SPRY4-IT1 (69) has been revealed to promote mRNA degradation through a similar mechanism, reducing the synthesis of tumor suppressor gene-encoded proteins, thereby promoting tumor proliferation and metastasis.

Additionally, as a molecular scaffold, lncRNA promotes the binding of RBPs to mRNA encoding ubiquitination-related proteins, regulating the synthesis of ubiquitin ligases, and thus the ubiquitin-mediated degradation of cancer-related proteins, which is another mechanism influencing the malignant biological behavior of cancer. The BCR protein complex is a major signaling molecule on the surface of B cells, which is involved in regulating B-cell activation, proliferation and differentiation. Aberrant activation of BCR signaling is a key factor in the proliferation of diffuse large B-cell lymphoma (DLBCL) cells (70,71). Polypyrimidine tract-binding protein 1 (PTBP1) is a multifunctional RBP that can promote the degradation of certain mRNAs by recruiting degradation complexes, or can prevent mRNA degradation by stabilizing its structure; the specific function depends on the binding site and other regulatory factors within the cell. Liu et al (72) identified that the lncRNA functional intergenic repeating RNA element (FIRRE) was highly expressed in DLBCL. After FIRRE binds to PTBP1, it promotes the binding of PTBP1 to the 3′ UTR of SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) mRNA, possibly leading to Smurf2 mRNA degradation by recruiting degradation complexes. Smurf2 is a ubiquitin ligase that promotes the ubiquitin-mediated degradation of BCR proteins. After Smurf2 mRNA is degraded, the synthesis of Smurf2 decreases, reducing the ubiquitin-mediated degradation of BCR proteins. This further maintains the abnormal activation of BCR signaling, ultimately promoting DLBCL proliferation (72).

lncRNA acting as a molecular scaffold to promote the binding of RBPs to mRNA is the most frequently reported mechanism of lncRNA-RBP interactions regulating mRNA stability in cancer research (Table I). In this mechanism, lncRNAs exert oncogenic or tumor-suppressive effects, or regulate chemotherapy sensitivity, by directly modulating the stability of mRNAs that have cancer-promoting, cancer-suppressing and chemotherapy sensitivity-influencing roles. On the other hand, it can regulate the stability of ubiquitin ligase genes, influencing the expression of tumor-suppressive or oncogenic genes, thus controlling the malignant biological behavior of tumors.

3. lncRNA competitively binds to RBPs, inhibiting the binding of RBPs to mRNA, thereby regulating mRNA stability

Competitive binding refers to the phenomenon where different molecules compete for the same binding site in biological systems, playing a key role in various biological processes, including enzyme activity regulation, receptor-ligand interactions, transcription factor-DNA binding and RBP-RNA interactions (73,74). In cancer, some lncRNAs bind to RBPs with different functions, blocking the binding of RBPs to mRNA. This competitive action is one of the mechanisms that regulates mRNA stability (Fig. 1B).

Competitive binding to RBPs that promote mRNA degradation

In cancer, after lncRNA binds to RBPs that promote mRNA degradation, it blocks the binding of RBPs to mRNA, preventing mRNA degradation, increasing mRNA stability and the synthesis of its encoded protein, thus affecting the malignant biological behavior of cancer. Zhou et al (75) found that the lncRNA six-transmembrane epithelial antigen of prostate 3 antisense RNA 1 (STEAP3-AS1) was highly expressed in colorectal cancer (CRC), and promoted CRC proliferation and metastasis. Mechanistically, STEAP3-AS1 competitively binds to YTHDF2, blocking its binding to STEAP3 mRNA, further inhibiting the YTHDF2-mediated degradation of STEAP3 mRNA (75); this increases STEAP3 mRNA stability, enhances STEAP3 protein synthesis, activates the Wnt/β-catenin signaling pathway, and promotes CRC cell proliferation, migration and invasion. In breast cancer studies, Tao et al (76) demonstrated that the lncRNA SCAMP1-TV2 could also promote tumor proliferation and metastasis through a similar mechanism (76).

Competitive binding to RBPs that prevent mRNA degradation

On the other hand, certain lncRNAs bind to RBPs that prevent mRNA degradation, blocking the binding of RBPs to mRNA, leading to mRNA degradation and reduced stability, playing an important role in regulating the malignant biological behavior of cancer. Heterogeneous nuclear ribonucleoprotein L (HNRNPL) is an RBP belonging to the heterogeneous nuclear ribonucleoprotein family, which can bind to the 3′ UTR of mRNA, forming a stable complex and preventing its degradation. In HCC studies, Wang et al (77) found that the lncRNA small nucleolar RNA host gene 6 could competitively bind to HNRNPL, blocking its binding to SET domain containing 7 (SETD7) mRNA, inhibiting the protective effect of HNRNPL on SETD7 mRNA, and promoting SETD7 mRNA degradation. The SETD7 protein has a tumor-suppressive role in HCC, and its reduced synthesis can enhance HCC migration and invasion, playing an important role in HCC progression (77). He et al (78) reported that the lncRNA LINC01093 was significantly downregulated in HCC, and its overexpression could significantly inhibit HCC progression. Mechanistically, LINC01093 competitively binds to IGF2BP1, blocking its binding to GLI1 mRNA, leading to the degradation of GLI1 mRNA without the protective effect of IGF2BP1. The GLI1 protein can upregulate cell cycle-related genes, promote cell transition from the G1 phase to the S phase, and enhance tumor cell proliferation; therefore, its reduced synthesis can significantly inhibit HCC proliferation and metastasis (78).

These studies revealed that lncRNAs, through competitive binding with different functional RBPs, can inhibit the binding of RBPs to mRNA, regulating mRNA stability and the synthesis of its encoded protein, thereby exerting oncogenic or tumor-suppressive effects in cancer (Table II).

4. lncRNA affects the nuclear-cytoplasmic localization of RBPs, influencing the amount of RBP bound to mRNA, thereby regulating mRNA stability

The normal distribution of proteins, RNA and other biological macromolecules between the nucleus and cytoplasm plays an important regulatory role in biological processes. When the nuclear-cytoplasmic distribution of these macromolecules is abnormal, it can lead to cellular dysfunction (79,80). In cancer, the abnormal nuclear-cytoplasmic distribution of lncRNAs and RBPs can affect mRNA stability, thereby influencing tumor progression. Chen et al (81) found that the lncRNA ASNR may have anti-apoptotic functions. The RBP AUF1 binds to the 3′ UTR region of Bcl-2 mRNA, promoting Bcl-2 mRNA degradation. Bcl-2 is an anti-apoptotic protein that serves a key role in apoptosis; however, when ASNR binds to AUF1 in the nucleus to form a complex, it prevents AUF1 from entering the cytoplasm, significantly altering its nuclear-cytoplasmic distribution, reducing Bcl-2 mRNA degradation and increasing Bcl-2 protein synthesis, thereby inhibiting tumor cell apoptosis (81). Conversely, Wang et al (82) demonstrated that after the lncRNA FIRRE binds to PTBP1 in the nucleus, it can promote the transfer of PTBP1 from the nucleus to the cytoplasm, forming a stable complex with Beclin 1 (BECN1) mRNA in the cytoplasm, preventing BECN1 mRNA degradation by enzymes, increasing its stability and enhancing BECN1 protein synthesis, thereby further promoting CRC proliferation and metastasis. This finding contrasts with that of Liu et al (72), but confirms that PTBP1, as a multifunctional RBP, affects mRNA stability differently depending on the binding site and intracellular regulatory factors. Through the aforementioned mechanisms, lncRNA alters the nuclear-cytoplasmic distribution of RBPs, thereby increasing or decreasing the binding of RBPs to mRNA, further regulating mRNA stability and affecting the malignant biological behavior of cancer (Fig. 1C; Table II).

5. lncRNA binds to RBPs that recognize m6A modifications, which then further identify and bind to m6A-modified mRNA, thereby regulating mRNA stability

RNA modification is an important mechanism of post-transcriptional regulation, with m6A modification being the most common type of RNA modification (83,84). m6A modification serves a crucial role in regulating mRNA stability and is an important mechanism for regulating gene expression (85,86). m6A reader proteins are a special class of RBPs that can recognize and bind m6A-modified mRNA, enhancing or reducing mRNA stability, and further influencing cellular functions (87). The main m6A reader proteins include the IGF2BP (88) family proteins (including IGF2BP1, IGF2BP2 and IGF2BP3) and the YTH (89,90) family proteins (including YTHDF1, YTHDF2 and YTHDF3). In cancer, lncRNAs bind to these m6A reader proteins, further recognizing and binding to m6A-modified mRNA, thereby regulating mRNA stability and influencing the malignant biological behavior and drug resistance of tumors. This is another mechanism for regulating mRNA stability (Fig. 2; Table III).

Yang et al found that the lncRNA LCAT1 was upregulated in lung cancer. After binding to IGF2BP2, LCAT1 further recognizes and binds to m6A-modified CDC6 mRNA, forming a stable complex that prevents CDC6 mRNA degradation, increasing its stability and the synthesis of its encoded protein. The CDC6 protein promotes cancer cell migration and invasion by affecting cytoskeleton reorganization, cell adhesion and matrix degradation, thereby promoting lung cancer cell proliferation and metastasis (91). Similarly, in breast cancer, the lncRNA KB-1980E6.3 may promote tumor proliferation and metastasis through a similar mechanism (92). Wang et al (93) demonstrated that the lncRNA UBA6-AS1 was downregulated in ovarian cancer, and its overexpression could inhibit tumor proliferation and metastasis. Mechanistically, UBA6-AS1 recruits IGF2BP1, and recognizes and binds to m6A-modified UBA6 mRNA, preventing its degradation, thus increasing UBA6 mRNA stability and the synthesis of its encoded protein. UBA6 promotes the ubiquitin-mediated degradation of cell cycle proteins and anti-apoptotic proteins, inhibiting ovarian cancer cell proliferation and metastasis (93).

Yang et al (94) reported that the lncRNA CBSLR, cystathionine-beta-synthase long non-coding RNA (CBSLR) could protect gastric cancer cells from ferroptosis, leading to chemotherapy resistance. Mechanistically, after CBSLR binds to the m6A reader protein YTHDF2, it promotes the recognition and binding of YTHDF2 to m6A-modified CBS mRNA. YTHDF2 further recruits the CCR4-NOT complex, leading to CBS mRNA degradation, reducing CBS protein synthesis and subsequently decreasing ACSL4 protein methylation, which leads to its degradation via the ubiquitin-proteasome pathway. This ultimately protects gastric cancer cells from ferroptosis, promoting chemotherapy resistance (94).

6. Potential therapeutic strategies targeting the molecular mechanisms by which lncRNA binding to RBPs regulates mRNA stability

In cancer, lncRNAs and RBPs regulate mRNA stability through the four aforementioned mechanisms. These findings not only improve the understanding of cancer progression and drug resistance mechanisms, but also provide a theoretical basis for developing new therapeutic strategies. In recent years, small molecule inhibitors, RNA interference technology and gene editing technology have been widely applied in molecular biology. By precisely regulating specific genes and protein functions, these technologies have advanced biomedical research (95–97). In addition, these technologies may have potential in cancer treatment. For example, small molecule inhibitors or RNA interference technology may be used to target lncRNAs, inhibit their binding to RBPs, or specifically inhibit RBPs to block their interactions with lncRNAs and mRNAs. This ultimately reduces the synthesis of oncogenic proteins or increases the synthesis of tumor-suppressive proteins, inhibiting tumor growth and metastasis, thereby playing a role in cancer treatment.

In a preclinical study by Wang et al (98), a small interfering (si)RNA targeting the lncRNA MALAT1 showed some efficacy in treating enzalutamide-resistant prostate cancer. In addition, in a breast cancer xenograft model, Wu et al (99) used the small molecule inhibitor 1c to bind to the RNA-binding domain of HuR, inhibiting the binding of HuR to TGFB2 and THBS1 mRNAs, which further inhibited breast cancer growth. Additionally, m6A reader proteins are key mechanisms in regulating mRNA stability. Inhibitors targeting m6A reader proteins, such as IGF2BP2 and YTHDF2, may significantly alter the biological behavior of cancer cells, inhibiting tumor growth and metastasis (100,101). Gene editing technology is also a potential means of treating cancer; for example, CRISPR/Cas9, which uses guide RNA and Cas9 protein complexes to precisely cut and edit DNA sequences. This can be used to knock out oncogenic lncRNA genes or repair mutated RBP genes, blocking the abnormal regulation of mRNA stability with high specificity and efficiency. Katsushima et al (102) found that knocking out the lnc-HLX-2-7 gene using CRISPR/Cas9 significantly inhibited tumor growth and prolonged the survival time of mice (102).

Although small molecule inhibitors, RNA interference technology and gene editing technology show great potential in cancer treatment and may provide novel options for precision cancer therapy, most research remains at the cellular and animal model stage, with only a few methods entering preclinical studies. These technologies face a series of challenges and limitations in practical application. Small molecule inhibitors lack selectivity, and the bioavailability and cellular delivery efficiency of drugs are key obstacles. The main challenge of RNA interference technology is to develop delivery systems that ensure siRNA or short hairpin RNA reaches target cells safely and effectively, and functions stably. Although gene editing technology can precisely modify genes, off-target effects, editing efficiency and long-term genetic impacts remain major challenges, and ethical issues also limit its clinical application. Therefore, these technologies have provided potential new areas for cancer treatment, but overcoming the aforementioned issues is necessary for them to be translated into safe and effective therapeutic approaches.

7. Conclusion and prospects

The interaction between lncRNAs and RBPs serves an important role in regulating gene expression, maintaining genome stability and participating in cell signal transduction, and it has a key role in cancer progression and drug resistance. In-depth analysis of lncRNA-RBP interactions is of great significance for revealing cancer molecular mechanisms, discovering new biomarkers and developing new therapeutic strategies. The present study reviewed the various mechanisms by which lncRNA regulates mRNA stability, including acting as a molecular scaffold to promote RBP binding to mRNA, competitively binding RBPs, affecting the nuclear-cytoplasmic localization of RBPs, and binding to m6A reader RBPs to regulate mRNA stability. These mechanisms affect the malignant biological behavior of cancer cells and drug resistance, highlighting their importance in cancer biology. Targeting these mechanisms via small molecule inhibitors, RNA interference technology and gene editing technology may provide new therapeutic options, but these still face challenges and limitations, such as the precise delivery of interfering molecules within cells, avoiding non-specific binding and reducing immune responses. This requires continuous optimization of existing technologies, development of more efficient delivery systems, and strengthening of ethical and safety regulations. Additionally, research on the impact of lncRNA-RBP interactions on mRNA stability in cancer remains limited in both scope and the range of cancers investigated, which constitutes a limitation of the present review. Future research should focus on large-scale screening methods, such as high-throughput sequencing or single-cell sequencing technologies, to more comprehensively reveal the network of lncRNA-RBP interactions and their specific roles in different types of cancer.

Acknowledgements

Not applicable.

Availability of data and materials

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Authors' contributions

NJZ and KW conceived the study. NJZ conducted the literature search and data analysis for inclusion in the review, drafted the manuscript and produced figures. KW edited and revised the manuscript. Data authentication is not applicable. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Figure 1. Mechanisms by which lncRNA acts as a molecular scaffold to promote RBP-mRNA binding, competitively binds RBPs, and influences the nuclear-cytoplasmic localization of RBPs to regulate mRNA stability. (A) lncRNA acts as a molecular scaffold for RBP-mRNA binding, promoting RBP-mRNA interactions to prevent or promote mRNA degradation. (B) lncRNA competitively binds different functional RBPs, blocking RBP-mRNA binding, thereby increasing or decreasing mRNA stability. (C) lncRNA regulates the subcellular localization of RBPs to control mRNA stability. In the nucleus, lncRNA binds to RBPs, preventing RBPs that promote mRNA degradation from entering the cytoplasm and transporting RBPs that increase mRNA stability to the cytoplasm, thereby reducing mRNA degradation and increasing mRNA stability. lncRNA, long non-coding RNA; RBP, RNA-binding protein. The image was drawn using Figdraw (www.figdraw.com).

Figure 2. Mechanism by which lncRNA regulates mRNA stability after binding to m6A reader RBPs. Some lncRNAs bind to IGF2BP family proteins, further recognizing and binding to m6A-modified mRNA to prevent its degradation and increase mRNA stability; on the other hand, some lncRNAs bind to YTH family proteins, recognizing and binding to m6A-modified mRNA, promoting its degradation and decreasing mRNA stability. lncRNA, long non-coding RNA; RBP, RNA-binding protein. The image was drawn using Figdraw (www.figdraw.com).

Table I. LncRNAs acts as a molecular scaffold for RBPs to bind mRNAs, thereby increasing mRNAs stability.

First author/s, year	LncRNAs	RBPs	mRNAs	Mechanism	Effect	(Refs.)	
Wang et al, 2019; Tuo et al, 2023;	EGFR-AS1, MRVI1-AS1,	HuR, CELF2,	EGFR, SKA1,	LncRNA acts as a	Increase mRNA	(41,44–49)	
Tian et al, 2021; Ren et al, 2022;	Linc-ROR, SNHG16,	HNRNPK, EIF4A3,	DEPDC1, RhoU,	molecular scaffold	stability and		
Yang and Hu, 2020; Zhu et al,	HOXC-AS3,	FUS, IGF2BP2,	FOXM1, TGFBR1,	for binding RBP to	promote cancer		
2022; Yang et al, 2014	LINC01232, GHET1	IGF2BP1	c-Myc	mRNA	proliferation		
Wu et al, 2020; Luo et al, 2020;	SNHG12, ZEB1-AS1,	IGF2BP2, ELAVL1,	CTNNB1, ZEB1,	LncRNA acts as a	Increase mRNA	(42,50–55)	
Ning et al, 2022; Wen et al, 2020;	NUTM2A-AS1,	SRSF1, PCBP2,	Trim37, RRM1,	molecular scaffold	stability and		
Wang et al, 2022; Chen et al, 2020;	LINC02535, ZFAS1,	U2AF2, ELAVL1,	HMGCR, FUT4,	for binding RBP to	promote cancer		
Lu et al, 2020	HOXB-AS1, LEF1-AS1	HNRNPL	LEF1	mRNA	metastasis		
Chen et al, 2023	LINC00659	FUS	SLC10A1	LncRNA acts as a molecular scaffold for binding RBP to mRNA	Increase mRNA stability and inhibit cancer progression	(43)	
Luo et al, 2022	ATXN8OS	ADAR	GLS2	LncRNA acts as a molecular scaffold for binding RBP to mRNA	Increase mRNA stability and inhibit cancer resistance	(65)	
Lu et al, 2021; Zhao et al, 2021	TINCR, SPRY4-IT1	STAU1	OAS1, TCEB1	LncRNA acts as a molecular scaffold to promote mRNA degradation through SMD pathway	It reduces mRNA stability and promotes cancer proliferation.	(68,69)	
Liu et al, 2022	FIRRE	PTBP1	Smurf2	LncRNA acts as a molecular scaffold for binding RBP to mRNA	It reduces mRNA stability and promotes cancer proliferation.	(72)	
LncRNAs, long non-coding RNAs; RBPs, RNA-binding proteins; EGFR-AS1, epidermal growth factor receptor antisense RNA 1; MRVI1-AS1, MRVI1 antisense RNA 1; Linc-ROR, long intergenic non-protein coding RNA, regulator of reprogramming; SNHG16, small nucleolar RNA host gene 16; HOXC-AS3, HOXC cluster antisense RNA 3; LINC01232, long intergenic nonprotein coding RNA 1232; GHET1, gastric carcinoma high expressed transcript 1; HuR, human antigen R; CELF2, CUGBP Elav-like family member 2; HNRNPK, heterogeneous nuclear ribonucleoprotein K; EIF4A3, eukaryotic translation initiation factor 4A3; FUS, fused in sarcoma; IGF2BP2, insulin-like growth factor 2 mRNA binding protein 2; IGF2BP1, insulin-like growth factor 2 mRNA binding protein 1; EGFR, epidermal growth factor receptor; SKA1, spindle and kinetochore associated complex subunit 1; DEPDC1, DEP domain containing 1; RhoU, Ras homolog family member U; FOXM1, forkhead box M1; TGFBR1, transforming growth factor beta receptor 1; SNHG12, small nucleolar RNA host gene 12; ZEB1-AS1, zinc finger E-box binding homeobox 1 antisense RNA 1; NUTM2A-AS1, NUTM2A antisense RNA 1; LINC02535, long intergenic non-protein coding RNA 2535; ZFAS1, ZNFX1 antisense RNA 1; HOXB-AS1, Homeobox antisense RNA 1; LEF1-AS1:LEF1 antisense RNA 1; ELAVL1, embryonic lethal, abnormal vision, Drosophila-Like 1; SRSF1, serine and arginine rich splicing factor 1; PCBP2, Poly (rC) binding protein 2; U2AF2, U2 small nuclear RNA auxiliary factor 2; HNRNPL, heterogeneous nuclear ribonucleoprotein L; CTNNB1, catenin beta 1; ZEB1, zinc finger E-box binding homeobox 1; RRM1, ribonucleotide reductase M1; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; FUT4, fucosyl-transferase 4; LEF1, lymphoid enhancer-binding factor 1; LINC00659, long intergenic non-protein coding RNA 659; SLC10A1, solute carrier family 10 member 1; ATXN8OS, ataxin-8 opposite strand; ADAR, adenosine deaminase acting on RNA; GLS2, glutaminase 2; TINCR, terminal differentiation-induced ncRNA; SPRY4-IT1, Sprouty RTK signaling antagonist 4 intronic transcript 1; FIRRE, functional intergenic repeating RNA element; STAU1, Staufen double-stranded RNA binding protein 1; PTBP1, polypyrimidine tract-binding protein 1; OAS1, oligoadenylate synthetase 1; TCEB1, transcription elongation factor B polypeptide 1; Smurf2, SMAD specific E3 ubiquitin protein ligase 2.

Table II. Mechanism by which LncRNAs competitively binds RBPs to mRNA and regulates mRNAs stability by affecting nucleoplasmic localization of RBPs.

First author/s, year	LncRNAs	RBPs	mRNAs	Mechanism	Effect	(Refs.)	
Zhou et al, 2022	STEAP3-AS1	YTHDF2	STEAP3	STEAP3-AS1 competitively	Prevent degradation of	(75)	
				binds to YTHDF2 and prevents			
				YTHDF2 from binding to			
				STEAP3 mRNA	STEAP3 mRNA		
Tao et al, 2020	SCAMP1-TV2	PUM2	INSM1	SCAMP1-TV2 binds to PUM2	Prevent degradation of	(76)	
				and prevents PUM2 from			
				binding to INSM1 mRNA	INSM1 mRNA		
Wang et al, 2021	SNHG6	HNRNPL	SETD7	SNHG6 competitively binds to	Reduce the stability of	(77)	
				HNRNPL and disrupts HNRNPL	SETD7 mRNA		
				binding to SETD7 mRNA			
He et al, 2019	LINC01093	IGF2BP1	GLI1	LINC01093 competitively binds to	Reduce the stability of	(78)	
				IGF2BP1 and disrupts IGF2BP1	GLI1 mRNA		
				binding to GLI1 mRNA			
Chen et al, 2016	ASNR	AUF1	Bcl-2	Lnc-ASNR binds to AUF1 and	Increase the stability of	(81)	
				prevents it from entering the	Bcl-2 mRNA		
				cytoplasm, reducing its			
				degradation of Bcl-2 mRNA			
Wang et al, 2022	FIRRE	PTBP1	BECN1	The combination of FIRRE and	Increase the stability of	(82)	
				PTBP1 promotes the transfer of	BECN1 mRNA		
				PTBP1 to the cytoplasm and			
				increases the binding of PTBP1			
				to BECN1 mRNA			
LncRNAs, long non-coding RNAs; RBPs, RNA-binding proteins; YTHDF2, YTH N6-methyladenosine RNA binding protein 2; STEAP3, six-transmembrane epithelial antigen of prostate 3; STEAP3-AS1, STEAP3 antisense RNA 1; SCAMP1-TV2, synaptic vesicle membrane protein 1 transcripts variant 2; PUM2, Pumilio RNA-binding family member 2; INSM1, insulinoma-associated 1; SNHG6, small nucleolar RNA host gene 6; HNRNPL, heterogeneous nuclear ribonucleoprotein L; SETD7, SET domain containing 7; LINC01093, long intergenic non-protein coding RNA 1093; IGF2BP1, insulin-like growth factor 2 mRNA binding protein 1; GLI1, glioma-associated oncogene 1; ASNR, antisense non-coding RNA in the INSR locus; AUF1, ARE/poly (U)-binding/degradation factor 1; Bcl-2, B-cell lymphoma 2; FIRRE, functional intergenic repeating RNA element; PTBP1, polypyrimidine tract-binding protein 1; BECN1, Beclin 1.

Table III. Mechanisms by which LncRNAs interact with RBPs that recognize m6A modifications to regulate mRNAs stability.

First author/s, year	LncRNAs	RBPs	mRNAs	Mechanism	Effect	(Refs.)	
Yang et al, 2022	LCAT1	IGF2BP2	CDC6	m6A methylation of CDC6 mRNA is maintained	Increase the stability of CDC6 mRNA	(91)	
Zhu et al, 2021	KB-1980E6.3	IGF2BP1	c-Myc	m6A methylation of c-Myc mRNA is maintained	Increase the stability of c-Myc mRNA	(92)	
Wang and Chen, 2022	UBA6-AS1	IGF2BP1	UBA6	m6A methylation of UBA6 mRNA is maintained	Increase the stability of UBA6 mRNA	(93)	
Yang et al, 2021	CBSLR	YTHDF2	CBS	Recognize and bind m6A-methylated CBS mRNA	Promote the degradation of CBS mRNA	(94)	
LncRNAs, long non-coding RNAs; RBPs, RNA-binding proteins; LCAT1, long-chain acyl-CoA synthetase 1; IGF2BP2, insulin-like growth factor 2 mRNA binding protein 2; CDC6, cell division cycle 6 homolog; KB-1980E6.3, also named AP002852.1; IGF2BP1, insulin-like growth factor 2 mRNA binding protein 1; UBA6-AS1, UBA6 antisense RNA 1; UBA6, ubiquitin-like modifier activating enzyme 6; CBSLR, cystathionine-beta-synthase long non-coding RNA; YTHDF2, YTH N6-methyladenosine RNA binding protein 2; CBS, cystathionine-beta-synthase.
==== Refs
References

1 Erber J Herndler-Brandstetter D Regulation of T cell differentiation and function by long noncoding RNAs in homeostasis and cancer Front Immunol 14 1181499 2023 10.3389/fimmu.2023.1181499 37346034
2 Liu X Li Y Jiang X Deng Y Ma C Yu Q Gao D Long non-coding RNA: Multiple effects on the differentiation, maturity and cell function of dendritic cells Clin Immunol 245 109167 2022 10.1016/j.clim.2022.109167 36272701
3 Mattick JS Amaral PP Carninci P Carpenter S Chang HY Chen LL Chen R Dean C Dinger ME Fitzgerald KA Long non-coding RNAs: Definitions, functions, challenges and recommendations Nat Rev Mol Cell Biol 24 430 447 2023 10.1038/s41580-022-00566-8 36596869
4 Fan J Li H Xie R Zhang X Nie X Shi X Zhan J Yin Z Zhao Y Dai B LncRNA ZNF593-AS alleviates contractile dysfunction in dilated cardiomyopathy Circ Res 128 1708 1723 2021 10.1161/CIRCRESAHA.120.318437 33550812
5 Huang H Yan J Lan X Guo Y Sun M Zhao Y Zhang F Sun J Lu S LncRNA WDR11-AS1 promotes extracellular matrix synthesis in osteoarthritis by directly interacting with RNA-binding protein PABPC1 to stabilize SOX9 expression Int J Mol Sci 24 817 2023 10.3390/ijms24010817 36614257
6 Liu F Cao Y Zhang C Su H Decreased DANCR contributes to high glucose-induced extracellular matrix accumulation in human renal mesangial cell via regulating the TGF-β/Smad signaling FASEB J 37 e22926 2023 10.1096/fj.202300146R 37052733
7 Yang Z Wan J Ma L Li Z Yang R Yang H Li J Zhou F Ming L Long non-coding RNA HOXC-AS1 exerts its oncogenic effects in esophageal squamous cell carcinoma by interaction with IGF2BP2 to stabilize SIRT1 expression J Clin Lab Anal 37 e24801 2023 10.1002/jcla.24801 36510377
8 Cai Z Shi Q Li Y Jin L Li S Wong LL Wang J Jiang X Zhu M Lin J LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein Sci Adv 9 eadi3821 2023 10.1126/sciadv.adi3821 37801505
9 Liu M Li H Li X Pan B Zhang J Pan Y Shen M Liu L A novel lncRNA FUAT1/TNS4 axis confers chemoresistance by suppressing reactive oxygen species-mediated apoptosis in gastric cancer Antioxid Redox Signal 41 24 41 2024 10.1089/ars.2023.0298 37658838
10 Zheng Z Wu M Li H Xu W Yang M Pan K Ni Y Jiang T Zheng H Jin X Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis BMC Med 21 132 2023 10.1186/s12916-023-02826-6 37013584
11 Bae H Coller J Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability Mol Cell 82 1467 1476 2022 10.1016/j.molcel.2022.03.032 35452615
12 Schuster SL Arora S Wladyka CL Itagi P Corey L Young D Stackhouse BL Kollath L Wu QV Corey E Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3′ untranslated region mutations Cell Rep 42 112840 2023 10.1016/j.celrep.2023.112840 37516102
13 Jia L Mao Y Ji Q Dersh D Yewdell JW Qian SB Decoding mRNA translatability and stability from the 5′ UTR Nat Struct Mol Biol 27 814 821 2020 10.1038/s41594-020-0465-x 32719458
14 Passmore LA Coller J Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression Nat Rev Mol Cell Biol 23 93 106 2022 10.1038/s41580-021-00417-y 34594027
15 Bednarek S Madan V Sikorski PJ Bartenschlager R Kowalska J Jemielity J mRNAs biotinylated within the 5′ cap and protected against decapping: New tools to capture RNA-protein complexes Philos Trans R Soc Lond B Biol Sci 373 20180167 2018 10.1098/rstb.2018.0167 30397103
16 Korn SM Ulshöfer CJ Schneider T Schlundt A Structures and target RNA preferences of the RNA-binding protein family of IGF2BPs: An overview Structure 29 787 803 2021 10.1016/j.str.2021.05.001 34022128
17 Mushtaq A Mir US Altaf M Multifaceted functions of RNA-binding protein vigilin in gene silencing, genome stability, and autism-related disorders J Biol Chem 299 102988 2023 10.1016/j.jbc.2023.102988 36758804
18 Yao ZT Yang YM Sun MM He Y Liao L Chen KS Li B New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer Cancer Commun (Lond) 42 117 140 2022 10.1002/cac2.12254 35019235
19 Li W Deng X Chen J RNA-binding proteins in regulating mRNA stability and translation: Roles and mechanisms in cancer Semin Cancer Biol 86 664 677 2022 10.1016/j.semcancer.2022.03.025 35381329
20 Qin H Ni H Liu Y Yuan Y Xi T Li X Zheng L RNA-binding proteins in tumor progression J Hematol Oncol 13 90 2020 10.1186/s13045-020-00927-w 32653017
21 Ouyang J Zhong Y Zhang Y Yang L Wu P Hou X Xiong F Li X Zhang S Gong Z Long non-coding RNAs are involved in alternative splicing and promote cancer progression Br J Cancer 126 1113 1124 2022 10.1038/s41416-021-01600-w 34750493
22 Schmitt AM Chang HY Long noncoding RNAs in cancer pathways Cancer Cell 29 452 463 2016 10.1016/j.ccell.2016.03.010 27070700
23 Shaath H Vishnubalaji R Elango R Kardousha A Islam Z Qureshi R Alam T Kolatkar PR Alajez NM Long non-coding RNA and RNA-binding protein interactions in cancer: Experimental and machine learning approaches Semin Cancer Biol 86 325 345 2022 10.1016/j.semcancer.2022.05.013 35643221
24 Ramesh-Kumar D Guil S The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer Semin Cancer Biol 86 18 31 2022 10.1016/j.semcancer.2022.05.009 35643219
25 Miao W Porter DF Lopez-Pajares V Siprashvili Z Meyers RM Bai Y Nguyen DT Ko LA Zarnegar BJ Ferguson ID Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation Cell 186 80 97.e26 2023 10.1016/j.cell.2022.12.004 36608661
26 Gebauer F Schwarzl T Valcárcel J Hentze MW RNA-binding proteins in human genetic disease Nat Rev Genet 22 185 198 2021 10.1038/s41576-020-00302-y 33235359
27 Herman AB Tsitsipatis D Gorospe M Integrated lncRNA function upon genomic and epigenomic regulation Mol Cell 82 2252 2266 2022 10.1016/j.molcel.2022.05.027 35714586
28 Nojima T Proudfoot NJ Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics Nat Rev Mol Cell Biol 23 389 406 2022 10.1038/s41580-022-00551-1 35079163
29 Knott GJ Bond CS Fox AH The DBHS proteins SFPQ, NONO and PSPC1: A multipurpose molecular scaffold Nucleic Acids Res 44 3989 4004 2016 10.1093/nar/gkw271 27084935
30 Chen Y Lu Y Yang L Ma W Dong Y Zhou S Liu N Gan W Li D LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner kinase-independent manner J Exp Clin Cancer Res 42 252 2023 10.1186/s13046-023-02837-4 37770905
31 Zhao P Ji MM Fang Y Li X Yi HM Yan ZX Cheng S Xu PP Janin A Wang CF A novel lncRNA TCLlnc1 promotes peripheral T cell lymphoma progression through acting as a modular scaffold of HNRNPD and YBX1 complexes Cell Death Dis 12 321 2021 10.1038/s41419-021-03594-y 33767152
32 Feng Y Zhang T Zhang Z Liang Y Wang H Chen Y Yu X Song X Mao Q Xia W The super-enhancer-driven lncRNA LINC00880 acts as a scaffold between CDK1 and PRDX1 to sustain the malignance of lung adenocarcinoma Cell Death Dis 14 551 2023 10.1038/s41419-023-06047-w 37620336
33 Zhang W Zhao J Deng L Ishimwe N Pauli J Wu W Shan S Kempf W Ballantyne MD Kim D INKILN is a novel long noncoding RNA promoting vascular smooth muscle inflammation via scaffolding MKL1 and USP10 Circulation 148 47 67 2023 10.1161/CIRCULATIONAHA.123.063760 37199168
34 Zhang Y Zhang H Zhang X Liu B CBR3-AS1 accelerates the malignant proliferation of gestational choriocarcinoma cells by stabilizing SETD4 Dis Markers 2022 7155525 2022 35655916
35 Xie M Ma T Xue J Ma H Sun M Zhang Z Liu M Liu Y Ju S Wang Z De W The long intergenic non-protein coding RNA 707 promotes proliferation and metastasis of gastric cancer by interacting with mRNA stabilizing protein HuR Cancer Lett 443 67 79 2019 10.1016/j.canlet.2018.11.032 30502359
36 Ni T Guo D Tan L Xiao Z Shi Y NPSR1-AS1 activates the MAPK pathway to facilitate thyroid cancer cell malignant behaviors via recruiting ELAVL1 to stabilize NPSR1 mRNA Cell Cycle 21 439 449 2022 10.1080/15384101.2021.1979773 35030041
37 Jalali S Gandhi S Scaria V Distinct and modular organization of protein interacting sites in long non-coding RNAs Front Mol Biosci 5 27 2018 10.3389/fmolb.2018.00027 29670884
38 Wang C Yang Y Zhang G Li J Wu X Ma X Shan G Mei Y Long noncoding RNA EMS connects c-Myc to cell cycle control and tumorigenesis Proc Natl Acad Sci USA 116 14620 14629 2019 10.1073/pnas.1903432116 31262817
39 Pan L Li Y Jin L Li J Xu A TRPM2-AS promotes cancer cell proliferation through control of TAF15 Int J Biochem Cell Biol 120 105683 2020 10.1016/j.biocel.2019.105683 31887411
40 Wang L Ye S Wang J Gu Z Zhang Y Zhang C Ma X HuR stabilizes lnc-Sox5 mRNA to promote tongue carcinogenesis Biochemistry (Mosc) 82 438 445 2017 10.1134/S0006297917040046 28371600
41 Wang A Bao Y Wu Z Zhao T Wang D Shi J Liu B Sun S Yang F Wang L Qu L Long noncoding RNA EGFR-AS1 promotes cell growth and metastasis via affecting HuR mediated mRNA stability of EGFR in renal cancer Cell Death Dis 10 154 2019 10.1038/s41419-019-1331-9 30770799
42 Wu D He X Wang W Hu X Wang K Wang M Long noncoding RNA SNHG12 induces proliferation, migration, epithelial-mesenchymal transition, and stemness of esophageal squamous cell carcinoma cells via post-transcriptional regulation of BMI1 and CTNNB1 Mol Oncol 14 2332 2351 2020 10.1002/1878-0261.12683 32239639
43 Chen B Xu X Wu W Zheng K Yu Y LINC00659 inhibits hepatocellular carcinoma malignant progression by blocking aerobic glycolysis through FUS recruitment and SLC10A1 modulation Anal Cell Pathol (Amst) 2023 5852963 2023 37234237
44 Tuo H Liu R Wang Y Yang W Liu Q Hypoxia-induced lncRNA MRVI1-AS1 accelerates hepatocellular carcinoma progression by recruiting RNA-binding protein CELF2 to stabilize SKA1 mRNA World J Surg Oncol 21 111 2023 10.1186/s12957-023-02993-z 36973749
45 Tian C Abudoureyimu M Lin X Chu X Wang R Linc-ROR facilitates progression and angiogenesis of hepatocellular carcinoma by modulating DEPDC1 expression Cell Death Dis 12 1047 2021 10.1038/s41419-021-04303-5 34741030
46 Ren L Fang X Shrestha SM Ji Q Ye H Liang Y Liu Y Feng Y Dong J Shi R LncRNA SNHG16 promotes development of oesophageal squamous cell carcinoma by interacting with EIF4A3 and modulating RhoU mRNA stability Cell Mol Biol Lett 27 89 2022 10.1186/s11658-022-00386-w 36221055
47 Yang Z Hu T Long noncoding RNA HOXC-AS3 facilitates the progression of invasive mucinous adenocarcinomas of the lung via modulating FUS/FOXM1 In Vitro Cell Dev Biol Anim 56 15 23 2020 10.1007/s11626-019-00414-8 31925650
48 Zhu L Liu Y Tang H Wang P FOXP3 activated-LINC01232 accelerates the stemness of non-small cell lung carcinoma by activating TGF-β signaling pathway and recruiting IGF2BP2 to stabilize TGFBR1 Exp Cell Res 413 113024 2022 10.1016/j.yexcr.2022.113024 35026283
49 Yang F Xue X Zheng L Bi J Zhou Y Zhi K Gu Y Fang G Long non-coding RNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-Myc mRNA stability FEBS J 281 802 813 2014 10.1111/febs.12625 24397586
50 Luo N Zhang K Li X Hu Y ZEB1 induced-upregulation of long noncoding RNA ZEB1-AS1 facilitates the progression of triple negative breast cancer by binding with ELAVL1 to maintain the stability of ZEB1 mRNA J Cell Biochem 121 4176 4187 2020 10.1002/jcb.29572 31922280
51 Ning X Zhao J He F Yuan Y Li B Ruan J lncRNA NUTM2A-AS1 targets the SRSF1/Trim37 signaling pathway to promote the proliferation and invasion of breast cancer Comput Math Methods Med 2022 3299336 2022 10.1155/2022/3299336 35959349
52 Wen D Huang Z Li Z Tang X Wen X Liu J Li M LINC02535 co-functions with PCBP2 to regulate DNA damage repair in cervical cancer by stabilizing RRM1 mRNA J Cell Physiol 235 7592 7603 2020 10.1002/jcp.29667 32324262
53 Wang L Ruan Y Wu X Zhou X lncRNA ZFAS1 promotes HMGCR mRNA stabilization via binding U2AF2 to modulate pancreatic carcinoma lipometabolism J Immunol Res 2022 4163198 2022 10.1155/2022/4163198 35846429
54 Chen R Zhang X Wang C LncRNA HOXB-AS1 promotes cell growth in multiple myeloma via FUT4 mRNA stability by ELAVL1 J Cell Biochem 121 4043 4051 2020 10.1002/jcb.29573 31886581
55 Lu X Qiao L Liu Y Long noncoding RNA LEF1-AS1 binds with HNRNPL to boost the proliferation, migration, and invasion in osteosarcoma by enhancing the mRNA stability of LEF1 J Cell Biochem 121 4064 4073 2020 10.1002/jcb.29579 31930565
56 Zhang M Sun Y Huang CP Luo J Zhang L Meng J Liang C Chang C Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases enzalutamide sensitivity to better suppress prostate cancer progression Cell Death Dis 12 855 2021 10.1038/s41419-021-03966-4 34545067
57 Dos Santos AF Fazeli G Xavier da Silva TN Friedmann Angeli JP Ferroptosis: Mechanisms and implications for cancer development and therapy response Trends Cell Biol 33 1062 1076 2023 10.1016/j.tcb.2023.04.005 37230924
58 Dixon SJ Lemberg KM Lamprecht MR Skouta R Zaitsev EM Gleason CE Patel DN Bauer AJ Cantley AM Yang WS Ferroptosis: An iron-dependent form of nonapoptotic cell death Cell 149 1060 1072 2012 10.1016/j.cell.2012.03.042 22632970
59 Tang D Chen X Kang R Kroemer G Ferroptosis: Molecular mechanisms and health implications Cell Res 31 107 125 2021 10.1038/s41422-020-00441-1 33268902
60 Jiang X Stockwell BR Conrad M Ferroptosis: Mechanisms, biology and role in disease Nat Rev Mol Cell Biol 22 266 282 2021 10.1038/s41580-020-00324-8 33495651
61 Qi R Bai Y Li K Liu N Xu Y Dal E Wang Y Lin R Wang H Liu Z Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs Drug Resist Updat 68 100960 2023 10.1016/j.drup.2023.100960 37003125
62 Zhang Q Deng T Zhang H Zuo D Zhu Q Bai M Liu R Ning T Zhang L Yu Z Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemoresistance in colorectal cancer Adv Sci (Weinh) 9 e2203357 2022 10.1002/advs.202203357 35978266
63 Zhang C Liu X Jin S Chen Y Guo R Ferroptosis in cancer therapy: A novel approach to reversing drug resistance Mol Cancer 21 47 2022 10.1186/s12943-022-01530-y 35151318
64 Wang Y Wu X Ren Z Li Y Zou W Chen J Wang H Overcoming cancer chemotherapy resistance by the induction of ferroptosis Drug Resist Updat 66 100916 2023 10.1016/j.drup.2022.100916 36610291
65 Luo J Bai R Liu Y Bi H Shi X Qu C Long non-coding RNA ATXN8OS promotes ferroptosis and inhibits the temozolomide-resistance of gliomas through the ADAR/GLS2 pathway Brain Res Bull 186 27 37 2022 10.1016/j.brainresbull.2022.04.005 35460867
66 Gowravaram M Schwarz J Khilji SK Urlaub H Chakrabarti S Insights into the assembly and architecture of a Staufen-mediated mRNA decay (SMD)-competent mRNP Nat Commun 10 5054 2019 10.1038/s41467-019-13080-x 31699982
67 Yadav DK Zigáčková D Zlobina M Klumpler T Beaumont C Kubíčková M Vaňáčová Š Lukavsky PJ Staufen1 reads out structure and sequence features in ARF1 dsRNA for target recognition Nucleic Acids Res 48 2091 2106 2020 10.1093/nar/gkz1163 31875226
68 Lu D Di S Zhuo S Zhou L Bai R Ma T Zou Z Chen C Sun M Tang J Zhang Z The long noncoding RNA TINCR promotes breast cancer cell proliferation and migration by regulating OAS1 Cell Death Discov 7 41 2021 10.1038/s41420-021-00419-x 33649294
69 Zhao L Jiang L Zhang M Zhang Q Guan Q Li Y He M Zhang J Wei M NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay Oncogene 40 4919 4929 2021 10.1038/s41388-021-01900-8 34163032
70 Eken JA Koning MT Kupcova K Sepúlveda Yáñez JH de Groen RAL Quinten E Janssen J van Bergen CAM Vermaat JSP Cleven A Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL J Exp Med 221 e20230941 2024 10.1084/jem.20230941 38512136
71 Schmitz R Wright GW Huang DW Johnson CA Phelan JD Wang JQ Roulland S Kasbekar M Young RM Shaffer AL Genetics and pathogenesis of diffuse large B-cell lymphoma N Engl J Med 378 1396 1407 2018 10.1056/NEJMoa1801445 29641966
72 Liu QH Dai GR Wu Y Wang XN Song MY Li XD Wu Z Xia RX LncRNA FIRRE stimulates PTBP1-induced Smurf2 decay, stabilizes B-cell receptor, and promotes the development of diffuse large B-cell lymphoma Hematol Oncol 40 554 566 2022 10.1002/hon.3004 35416325
73 Nag S Goswami B Das Mandal S Ray PS Cooperation and competition by RNA-binding proteins in cancer Semin Cancer Biol 86 286 297 2022 10.1016/j.semcancer.2022.02.023 35248729
74 Liu Y Xue M Du S Feng W Zhang K Zhang L Liu H Jia G Wu L Hu X Competitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT Nat Commun 10 1637 2019 10.1038/s41467-019-09649-1 30967542
75 Zhou L Jiang J Huang Z Jin P Peng L Luo M Zhang Z Chen Y Xie N Gao W Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA Mol Cancer 21 168 2022 10.1186/s12943-022-01638-1 35986274
76 Tao W Ma J Zheng J Liu X Liu Y Ruan X Shen S Shao L Chen J Xue Y Silencing SCAMP1-TV2 inhibited the malignant biological behaviors of breast cancer cells by interaction with PUM2 to facilitate INSM1 mRNA degradation Front Oncol 10 613 2020 10.3389/fonc.2020.00613 32670859
77 Wang H Ma P Liu P Guo D Liu Z Zhang Z lncRNA SNHG6 promotes hepatocellular carcinoma progression by interacting with HNRNPL/PTBP1 to facilitate SETD7/LZTFL1 mRNA destabilization Cancer Lett 520 121 131 2021 10.1016/j.canlet.2021.07.009 34252487
78 He J Zuo Q Hu B Jin H Wang C Cheng Z Deng X Yang C Ruan H Yu C A novel, liver-specific long noncoding RNA LINC01093 suppresses HCC progression by interaction with IGF2BP1 to facilitate decay of GLI1 mRNA Cancer Lett 450 98 109 2019 10.1016/j.canlet.2019.02.033 30790682
79 Puertollano R Ferguson SM Brugarolas J Ballabio A The complex relationship between TFEB transcription factor phosphorylation and subcellular localization EMBO J 37 e98804 2018 10.15252/embj.201798804 29764979
80 Shen Y Zou Y Li J Chen F Li H Cai Y CDK5RAP3, a novel nucleoplasmic shuttle, deeply regulates hsf1-mediated heat stress response and protects mammary epithelial cells from heat injury Int J Mol Sci 21 8400 2020 10.3390/ijms21218400 33182370
81 Chen J Liu L Wei G Wu W Luo H Yuan J Luo J Chen R The long noncoding RNA ASNR regulates degradation of Bcl-2 mRNA through its interaction with AUF1 Sci Rep 6 32189 2016 10.1038/srep32189 27578251
82 Wang Y Li Z Xu S Li W Chen M Jiang M Fan X LncRNA FIRRE functions as a tumor promoter by interaction with PTBP1 to stabilize BECN1 mRNA and facilitate autophagy Cell Death Dis 13 98 2022 10.1038/s41419-022-04509-1 35110535
83 He PC Wei J Dou X Harada BT Zhang Z Ge R Liu C Zhang LS Yu X Wang S Exon architecture controls mRNA m6A suppression and gene expression Science 379 677 682 2023 10.1126/science.abj9090 36705538
84 Deng X Qing Y Horne D Huang H Chen J The roles and implications of RNA m6A modification in cancer Nat Rev Clin Oncol 20 507 526 2023 10.1038/s41571-023-00774-x 37221357
85 Uzonyi A Dierks D Nir R Kwon OS Toth U Barbosa I Burel C Brandis A Rossmanith W Le Hir H Exclusion of m6A from splice-site proximal regions by the exon junction complex dictates m6A topologies and mRNA stability Mol Cell 83 237 251.e7 2023 10.1016/j.molcel.2022.12.026 36599352
86 Chen J Zhang H Xiu C Gao C Wu S Bai J Shen Q Yin T METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner Cancer Lett 565 216222 2023 10.1016/j.canlet.2023.216222 37196908
87 Fagre C Gilbert W Beyond reader proteins: RNA binding proteins and RNA modifications in conversation to regulate gene expression Wiley Interdiscip Rev RNA 15 e1834 2024 10.1002/wrna.1834 38444048
88 Elcheva IA Gowda CP Bogush D Gornostaeva S Fakhardo A Sheth N Kokolus KM Sharma A Dovat S Uzun Y IGF2BP family of RNA-binding proteins regulate innate and adaptive immune responses in cancer cells and tumor microenvironment Front Immunol 14 1224516 2023 10.3389/fimmu.2023.1224516 37503349
89 Stowell JAW Webster MW Kögel A Wolf J Shelley KL Passmore LA Reconstitution of targeted deadenylation by the Ccr4-not complex and the YTH domain protein Mmi1 Cell Rep 17 1978 1989 2016 10.1016/j.celrep.2016.10.066 27851962
90 Sikorski V Selberg S Lalowski M Karelson M Kankuri E The structure and function of YTHDF epitranscriptomic m6A readers Trends Pharmacol Sci 44 335 353 2023 10.1016/j.tips.2023.03.004 37069041
91 Yang J Qian X Qiu Q Xu L Pan M Li J Ren J Lu B Qiu T Chen E LCAT1 is an oncogenic LncRNA by stabilizing the IGF2BP2-CDC6 axis Cell Death Dis 13 877 2022 10.1038/s41419-022-05316-4 36257938
92 Zhu P He F Hou Y Tu G Li Q Jin T Zeng H Qin Y Wan X Qiao Y A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability Oncogene 40 1609 1627 2021 10.1038/s41388-020-01638-9 33469161
93 Wang Y Chen Z Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA Bioengineered 13 178 189 2022 10.1080/21655979.2021.2011640 34951345
94 Yang H Hu Y Weng M Liu X Wan P Hu Y Ma M Zhang Y Xia H Lv K Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer J Adv Res 37 91 106 2021 10.1016/j.jare.2021.10.001 35499052
95 Afrin H Geetha Bai R Kumar R Ahmad SS Agarwal SK Nurunnabi M Oral delivery of RNAi for cancer therapy Cancer Metastasis Rev 42 699 724 2023 10.1007/s10555-023-10099-x 36971908
96 Chan YT Lu Y Wu J Zhang C Tan HY Bian ZX Wang N Feng Y CRISPR-Cas9 library screening approach for anti-cancer drug discovery: Overview and perspectives Theranostics 12 3329 3344 2022 10.7150/thno.71144 35547744
97 Fan J Xu Y Wen X Ge S Jia R Zhang H Fan X A cohesin-mediated intrachromosomal loop drives oncogenic ROR lncRNA to accelerate tumorigenesis Mol Ther 27 2182 2194 2019 10.1016/j.ymthe.2019.07.020 31451355
98 Wang R Sun Y Li L Niu Y Lin W Lin C Antonarakis ES Luo J Yeh S Chang C Preclinical study using Malat1 small interfering RNA or androgen receptor splicing variant 7 degradation enhancer ASC-J9® to suppress enzalutamide-resistant prostate cancer progression Eur Urol 72 835 844 2017 10.1016/j.eururo.2017.04.005 28528814
99 Wu X Ramesh R Wang J Zheng Y Armaly AM Wei L Xing M Roy S Lan L Gao FP Small molecules targeting the RNA-binding protein HuR inhibit tumor growth in xenografts J Med Chem 66 2032 2053 2023 10.1021/acs.jmedchem.2c01723 36690437
100 Weng H Huang F Yu Z Chen Z Prince E Kang Y Zhou K Li W Hu J Fu C The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia Cancer Cell 40 1566 1582.e10 2022 10.1016/j.ccell.2022.10.004 36306790
101 Xu F Li J Ni M Cheng J Zhao H Wang S Zhou X Wu X FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2 Mol Cancer 20 45 2021 10.1186/s12943-021-01340-8 33658012
102 Katsushima K Lee B Kunhiraman H Zhong C Murad R Yin J Liu B Garancher A Gonzalez-Gomez I Monforte HL The long noncoding RNA lnc-HLX-2-7 is oncogenic in group 3 medulloblastomas Neuro Oncol 23 572 585 2021 10.1093/neuonc/noaa235 33844835
