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Discov Oncol
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10.1007/s12672-024-01296-3
Research
Unveiling the role of PSMA5 in glioma progression and prognosis
Liu Wei 12
Jia Bo 12
Wang Zan 12
Li Chengcai 12
Li Nanding 12
Tang Jie tangjiett@163.com

23
Wang Jiwei 57503001@hebmu.edu.cn

12
1 grid.452458.a Department of Neurosurgery, The First Hospital of Hebei Medical University, Shijiazhuang, China
2 grid.24696.3f 0000 0004 0369 153X Department of Neurosurgery, Hebei Hospital of Xuanwu Hospital Capital Medical University, Shijiazhuang, China
3 https://ror.org/013xs5b60 grid.24696.3f 0000 0004 0369 153X Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
6 9 2024
6 9 2024
12 2024
15 41419 6 2024
2 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Glioma is the most aggressive intracranial malignancy and is associated with poor survival rates and limited quality of life, impairing neuropsychological function and cognitive competence in survivors. The Proteasome Subunit Alpha Type-5 (PSMA5) is a multicatalytic proteinase complex that has been linked with tumor progression but is rarely reported in glioma. This study investigates the expression pattern, prognostic characteristics, and potential biological functions of PSMA5 in glioma. PSMA5 was significantly overexpressed in 28 types of cancer when compared to normal tissue. Furthermore, elevated levels of PSMA5 were observed in patients with wild-type isocitrate dehydrogenase 1 and exhibited a positive correlation with tumor grade. It was also found to be a standalone predictor of outcomes in glioma patients. Additionally, inhibiting PSMA5-induced cell cycle arrest may provide a therapeutic option for glioma.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-024-01296-3.

Keywords

Glioma
PSMA5
Immunotherapy
Cell cycle
Prognostic signature
http://dx.doi.org/10.13039/501100003787 Natural Science Foundation of Hebei Province No. H2023206403 No. H2023206403 No. H2023206403 No. H2023206403 No. H2023206403 No. H2023206403 No. H2023206403 Liu Wei Jia Bo Wang Zan Li Chengcai Li Nanding Tang Jie Wang Jiwei issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Over the past three decades, there has been a 12% rise in the annual occurrence of primary malignant brain tumors [1–3]. Gliomas, the most prevalent type of central nervous system tumors, are associated with unfavorable prognoses and low survival rates. To enhance the precision in defining distinct glioma entities, the World Health Organization updated the classification of diffuse gliomas, incorporating both histological and molecular characteristics in 2021.This revised classification delineates lower-grade gliomas (LGG, grades II and III) and glioblastomas (GBM, grade IV). Furthermore, these tumors are categorized based on their isocitrate dehydrogenase (IDH) mutation status and 1p/19q codeletion status [4–9]. Higher grade tumors are more invasive. Glioblastoma, the most aggressive type of brain cancer, accounts for more than half of newly diagnosed cases. Despite years of research and development of therapeutic interventions, including surgical procedures and chemotherapy, a definitive and successful treatment remains elusive [4, 9]. The absence of well-defined tumor boundaries, the strategic positioning of the tumor mass, and the existence of chemo- and radio-resistant tumor stem cells collectively contribute to unfavorable prognostic outcomes.The median survival of glioma patients is only 12 to 14 months [10–12].

The intracellular protein degradation pathway, ubiquitin-proteasomes,is responsible for the degradation of more than 80% of intracellular proteins [13–15].The proteasome is found in the nucleus and cytoplasm of higher eukaryotic cells as a component of the ubiquitin–proteasome system. This crucial proteolytic mechanism mainly relies on the proteasome, a multi-subunit protein complex. There is a central cylindrical particle, the 20S, and a regulator, the 19S, within the 26S proteasome.The 20S consists of seven α (PSMA1-7) or β (PSMB1-7) subunits. PSMA5 is a constituent of the 20S proteasome core complex and serves a crucial function in interacting with the 19S regulatory complex.A proteasome catalyzes the rapid degradation of ubiquitinated proteins [16]. The proteasome inhibitor thus plays an essential role in mammalian cell proliferation as a tumor suppressor and negative growth regulator [17–19].Various cancers, including colorectal [20], prostate [21], and breast [22, 23], have been linked to this association. Moreover, reversible 26S proteasome inhibitors have been available in clinical practice as an anti-tumor drug for a while [24, 25]. Molecular targets such as the ubiquitin–proteasome system have become promising for cancer therapy due to their key roles in cell cycle control, apoptosis regulation, and protein degradation. Moreover, PSMA5 has been associated with unfavorable prognostic outcomes in multiple cancer types. A previous [26] study has shown a significantly elevated expression of PSMA5 in pulmonary neuroendocrine tumors compared to normal tissues [27]. Similarly, prostate cancer tumorigenesis is facilitated by up-regulated PSMA5 expression [28].

As yet, limited knowledge exists regarding the clinical significance and biological role of PSMA5 in gliomas. In this study, PSMA5 expression in gliomas was analyzed utilizing two distinct RNA sequencing databases, namely the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (CGGA). The investigation assessed the expression patterns of PSMA5 in gliomas, examined its prognostic significance, and delved into its functional role. An extensive analysis of PSMA5 explores its potential as a therapeutic target or prognostic biomarker.

Materials and methods

Patients and datasets

Pan-cancer RNA-seq data downloaded from UCSC XENA were included in our study. The glioma samples were obtained from TCGA and CGGA datasets for analysis. Immunohistochemical sections of brain tissues, including glioma and normal brain samples, were obtained from The First Hospital of Hebei Medical University. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The collection of all human samples in this study was approved by ethics board of The First Hospital of Hebei Medical University (No. 20221107).

Immune cell infiltration

Scores for immune cell infiltration from TCGA were derived from a previously published study using the ssGSEA analytical tool [29, 30]. Two groups of samples were identified based on the median PSMA5 expression in the TCGA glioma sample (high and low expression).

Functional enrichment analysis

We conducted a comparative analysis of the median mRNA expression profiles between groups with high and low expression levels using the DESeq2 R package in order to identify differentially expressed genes (DEGs).Functional enrichment analysis was performed using DEGs with logFC > 1 and padj < 0.05 threshold.GSEA using ClusterProfiler (version 3.14.3) was conducted to explore functional and pathway variances among groups with high and low expression levels of PSMA5.The "Network" module (version: 4.3) of BioGRID (https://thebiogrid.org) was utilized as a tool for conducting the analysis.

Cell culture and transfection

The U251 human glioma cell lines were obtained from the American Type Culture Collection and cultured in DMEM (Invitrogen, USA) supplemented with 10% PBS at 37 ℃ in a 5% CO2 environment. The impact of PSMA5 on U251 cells was assessed using PSMA5 siRNA 5ʹ-GGUGGUGAACCGAGUGUUU-3ʹ.

Cell proliferation assay

Cell proliferation was assessed by utilizing the Cell Counting Kit-8 in accordance with the guidelines provided by the manufacturer. Specifically, 2000 cells were plated in a 96-well plate and incubated for 24, 48, and 72 h. Absorbance was detected at 450 nm to evaluate the results.

Cell cycle analysis

Cells were transfected with si-control or si-PSMA5 for 24 h, and the percentage of cells in each cell cycle phase was detected as previously described [31].

Western blot analysis

To investigate the protein expression related to PSMA5 in glioma cells, we conducted Western blot analyses. The cells were lysed in RIPA buffer (Thermo Fisher Scientific, USA), which was supplemented with protease and phosphatase inhibitors, in order to identify the proteins involved in PSMA5 expression. Following this, the lysate was centrifuged at 12,000 g for 15 min at a temperature of 4 °C to ascertain protein concentrations. We procured a BCA protein assay kit from Thermo Fisher Scientific for this purpose. Subsequently, 30 µg of protein was separated using SDS-PAGE on 10% polyacrylamide gels. This was then transferred to PVDF membranes (Millipore, USA).The membranes were subjected to a blocking process for a duration of one hour at room temperature, utilizing 5% nonfat milk in a TBST buffer (Tris-buffered saline with 0.1% Tween-20). Prior to the incubation of the antibodies, a membrane was meticulously trimmed based on the molecular weight of the antibodies, thereby facilitating various antibody incubations. The membranes were then incubated with primary antibodies against PSMA5 (cat. no. 31384–1-AP; 1:1,500 dilution; Proteintech), CDK1(cat. no. 65182–1-Ig; 1:1,000 dilution; Proteintech) and CDK2(cat. no. 83635–4-RR; 1:1,0000 dilution; Proteintech) using TBST containing 5% BSA. Subsequently, the membranes were washed with TBST and incubated with HRP-conjugated secondary antibodies at room temperature. The visualization of protein bands was facilitated by the utilization of an enhanced chemiluminescence (ECL) detection system from Thermo Fisher Scientific. Subsequently, the quantification of these protein bands was accomplished using ImageJ software (NIH, USA). The normalization factor employed for the determination of relative protein expression levels was GAPDH(cat. no. 60004–1-Ig; 1:20,0000 dilution; Proteintech).

Statistical analysis

Statistical analyses were done using R (version 3.6.3). PSMA5 expression was compared in binary groups using student’s test and in multiple groups using one-way ANOVA. Predictive value was assessed using cox regression analysis and Kaplan–Meier method. A nomogram was created using RMS R package (version 5.1–3) based on clinical characteristics and calibration plots. Data presented as mean ± standard deviation from three independent experiments. P < 0.05 was considered statistically significant.

Result

PSMA5 expression in pan-cancers and Glioma

To explore the involvement of PSMA5 in various types of cancer, RNA-seq data from TCGA and GTEx were acquired from UCSC XENA. PSMA5 exhibited a significant upregulation in 28 cancer types when compared to normal tissue, including low-grade glioma (LGG) and glioblastomas (GBM) as shown in Fig. 1A. Subsequently, an immunohistochemical analysis was performed to assess PSMA5 expression in normal brain tissue and 15 glioma tissues, as depicted in Fig. 1B. The findings revealed an elevated expression of PSMA5 in glioma tissues relative to normal brain tissues, as illustrated in Fig. 1C.Fig. 1 Aberrant expression of PSMA5 in different tumors and normal tissues (A) A comparison of PSMA5 expression levels in normal and pan-cancer samples. B Immunohistochemical detection of PSMA5 protein in normal brain tissue and gliomas. C Protein expression level of PSMA5 in normal brain tissue and gliomas *P < 0.05

Subtypes of gliomas and PSMA5 expression

In order to ascertain the correlation between PSMA5 expression and glioma subtypes, a total of 310 glioma samples from the Chinese Glioma Genome Atlas (CGGA) RNA-sequencing dataset were acquired for analysis.PSMA5 mRNA was overexpressed in high-grade glioma (Fig. 2A) and IDH1 wild-type (Fig. 2C). Simailar results were validated in 691 samples from the TCGA datasets (Fig. 2B, D).Fig. 2 A comparison of CGGA and TCGA datasets for expression of PSMA5. A, B High-grade gliomas showed significantly higher levels of PSMA5 expression than low-grade ones (C, D) IDH wildtype gliomas showed significantly higher levels of PSMA5 expression than mutant ones

PSMA5 serves as an autonomous predictive marker in patients with glioma

A Kaplan–Meier survival curve analysis was conducted to investigate the relationship between PSMA5 mRNA expression and survival duration. The CGGA and TCGA datasets analysis results revealed that higher PSMA5 expression indicated remarkably shorter overall survival within all grade gliomas (Fig. 3A, B).The prognostic significance of PSMA5 in glioma patients was assessed through ROC curve analysis, revealing that the area under the curve (AUC) values for PSMA5 expression in predicting survival were 0.706 (1 year), 0.766 (3 years), and 0.781 (5 years) in CGGA datasets (Fig. 3C), and 0.750 (1 year), 0.774 (3 years), and 0.757 (5 years) in TCGA datasets (Fig. 3D).Fig. 3 The upregulation of PSMA5 in glioma patients was correlated with a diminished overall survival outcome.Kaplan–Meier survival analysis of overall survival stratified by PSMA5 expression in CGGA (A) and TCGA (B).The diagnostic efficacy of PSMA5 in gliomas analyzed by ROC in CGGA (C) and TCGA (D)

Subsequently, independent risk factors were assessed through univariate and multivariate Cox regression analyses. PSMA5 expression (P < 0.001), age (P < 0.001), tumor grade (P < 0.001), and IDH1 status (P < 0.001) were determined as independent risk factors in glioma samples from the CGGA and TCGA datasets (Fig. 4A, B). In the multivariate regression analysis, PSMA5 expression remained a significant independent prognostic factor (CGGA: P < 0.01, TCGA: P = 0.032, Fig. 4C), along with tumor grade (CGGA: P < 0.01, TCGA: P < 0.01, Fig. 4D).Fig. 4 PSMA5 was an independent biomarker in glioma diagnosis.Univariate analyses of overall survival in the CGGA (A) and TCGA (B),multivariate analyses of overall survival in the CGGA (C) and TCGA (D)

Functional analysis of PSMA5

In order to investigate the impact of PSMA5 on cellular function, a median difference in PSMA5 expression was observed between groups with high and low expression levels. A total of 276 Differentially Expressed Genes (DEGs) from the Chinese Glioma Genome Atlas (CGGA) datasets were identified as statistically significant, with 95 genes upregulated and 181 genes downregulated in the PSMA5 high-expression group compared to the low-expression group (|log fold change (logFC)|> 1.0, P < 0.05) (Fig. 5A).We also got 2264 DEGs from TCGA datasets, including 1089 upregulated and 1174 down-regulated(|log fold change (logFC)|> 1.0, P < 0.05) (Fig. 5B).The heat map depicted the 20 most up-regulated and 20 most down-regulated Differentially Expressed Genes (DEGs) in the comparison of high- and low-expressed groups of PSMA5 in the Cancer Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets (Fig. 5C, D).Fig. 5 Identification differential expressed genes between PSMA5 high-expressed and low-expressed groups in CGGA and TCGA.Volcano plot of differentially expressed genes in CGGA (A) and TCGA (B). Heat map of the top 20 differentially expressed genes in CGGA (C) and TCGA (D)

Hereafter,an analysis of the GO terms and GSEA was performed on PSMA5 in order to determine its biological function. GO annotation revealed that high levels of PSMA5 were positively associated with mitotic sister chromatid segregation, B cell-mediated immunity, adaptive immune response and humoral immune response (Fig. 6A, B). GSEA revealed that high levels of PSMA5 were positively associated with G2M checkpoint, epithelial-mesenchymal transition, E2F target and TNF signaling via NFKB in the CGGA and TCGA datasets (Fig. 6C, D).Fig. 6 Gene enrichment analysis related to PSMA5. A Gene Ontology (GO) analysis of differential expressed genes between PSMA5 high-expressed and low-expressed groups in CGGA (B) Gene Ontology (GO) analysis of differential expressed genes between PSMA5 high-expressed and low-expressed groups in TCGA (C) GSEA analysis of differential expressed genes between PSMA5 high-expressed and low-expressed groups in CGGA (D) GSEA analysis of differential expressed genes between PSMA5 high-expressed and low-expressed groups in TCGA

The relationship between immune cell infiltration and PSMA5 expression

The expression levels of PSMA5 in the glioma microenvironment were found to be significantly associated with the degree of immune cell infiltration as determined by single-sample gene set enrichment analysis (SSGSEA), as indicated by Spearman correlation analysis (Fig. 7A).The expression of PSMA5 correlated significantly positively with macrophage infiltration and Th2 cell infiltration and adversely with pDC (plasmaacytoid DC) cells(Fig. 7B, C).These results indicated that there is a strong correlation between high PSMA5 expression and an immune-activated state of glioma.Fig. 7 Correlation between immune cell infiltration and PSMA5 expression in gliomas (A) A comparison of immune cell infiltration levels between high and low PSMA5 expression groups in gliomas from The Cancer Genome Atlas. B The forest plots showed PSMA5 correlated positively with 14 immune cells, and negatively with 10 immune cell subtypes. C Immune cell infiltration levels and PSMA5 expression are correlated, with red denoting positive correlation, green denoting negative correlation, and deep colors indicate stronger correlations

PSMA5 promotes proliferation and induces cell cycle arrest of glioma cells in vitro

Furthermore, the correlation of PSMA5 with CDKs expression was investigated. PSMA5 was significantly associated with CDKs (Fig. 8A, B). Then, we searched the BioGRID4.3 database and found a physical interaction between CDK1, CDK2 and PSMA5 proteins well-known for their role in cell cycle regulation, mitotic regulation, and tumorigenesis (Fig. 8C). The results suggested that PSMA5 played a tumor-promoting role in cancers by driving the cell cycle.Fig. 8 The correlation between PSMA5 and CDKs. A The expression levels of PSMA5 exhibited a positive correlation with those of CDK1, CDK2, CDK3, CDK4, CDK5, and CDK7 in the Chinese Glioma Genome Atlas (CGGA) dataset. B The expression of PSMA5 were positively correlated with CDK1,CDK2,CDK3,CDK4,CDK5 and CDK7 in TCGA. C An analysis of the PSMA5-protein interactions carried out by BioGRID

We performed an search of the database (https://www.proteinatlas.org) to examine the expression levels of PSMA5 across various glioma cell lines (Fig. 1S). Our analysis revealed that PSMA5 expression is comparatively elevated in U251 and U87MG cell lines. To investigate the functional of PSMA5, we employed siRNA to silence endogenous PSMA5. Western blot analyses indicated a significant reduction in CDK1 and CDK2 expression in U251 cells (Fig. 9A). Furthermore, the depletion of PSMA5 inhibited the proliferative capacity of U251 cells and induced G2/M cell cycle arrest post-transfection with siRNA (Fig. 9B, C).Comparable results were also observed in the U87MG cell line,the knockdown of PSMA5 resulted in a reduction in the expression levels of CDK1 and CDK2 (Fig. 2S A), concomitant with a decrease in glioma cell proliferation (Fig. 2S B) and induction of G2/M cell cycle arrest (Fig. 2S C). These findings underscore the critical role of PSMA5 in regulating cell proliferation and cycle progression.Fig. 9 Downregulation of PSMA5 inhibited the proliferation,caused cell cycle arrest and altered gene expression associated with cell cycle in vitro. APSMA5,CDK1 and CDK2 expression are decreased in U251 after the addition of PSMA5 siRNA. B CCK-8 assays demonstrating PSMA5 knockdown resulted in U251 inhibition. C Downregulation of PSMA5 induced the G2/M cell cycle arrest in U251. *P < 0.05

Discussion

The ubiquitin–proteasome system (UPS), a major celluar protein degradation system, regulates a variety of cellular processes, UPS is one of the primary mechanisms by which proteins are degraded in the human body and is mainly responsible for the degradation of intracellular proteins [32, 33]. Four steps are involved: substrate, labeling, crushing and resorption. As tumor cell growth is particularly dependent on the UPS, this pathway is a potential target of antitumor therapy [32]. At present, proteasome inhibitors mainly focus on the third link, namely crushing.

Acting as a supervisor, the 26S proteasome clears unnecessary and improperly folded transcription factors or enzymes and maintains the stability of the intracellular environment [34, 35]. As a key part of the proteasome, the aberrant expression of PSMA5 induce abnormal activity. Abnormal protein degradation causes a variety of physiological disturbances, leading to diseases such as tumors [36, 37]. Previous studies suggested that proteasome activity is abnormally elevated in multiple tumor cells [38]. It is still unproven how PSMA5 is expressed in different types of human cancer and whether it has a prognostic significance. TCGA datasets revealed that PSMA5 was hyperexpressed in 28 types of tumor tissues compared to normal tissues, suggesting that PSMA5 could be an oncogene. In addition, we examined the relationship between PSMA5 overexpression and clinical parameters or prognosis. Glioma patients expressing high levels of PSMA5 had a poorer overall survival according to a survival analysis. In a multivariate Cox regression analysis, it was found that elevated PSMA5 expression was significantly correlated with a poorer prognosis. It would therefore appear that PSMA5 is a new adverse prognostic factor for patients with gliomas.

We further explored the potential regulatory mechanisms of PSMA5 and found PSMA5 was associated with cell cycle and immune cellular responses. Accumulating evidence has indicated that higher macrophages facilitated the progression of glioma [39–41]. In the analysis of immune cell infiltration, the levels of macrophages and T helper 2 cells were found to be significantly increased in glioma tissue compared to normal tissue. Moreover, higher expression of PSMA5 was positively associated with higher macrophages and T helper 2 cell which indicated that PSMA5 play a key role in regulating tumor immunology.

Previous studies have shown that PSMA5 takes part in the proliferation, invasiveness, and apoptosis of prostate cancer cells. Multiple studies have demonstrated an increase in PSMA5 expression in both human prostate cancer tissues and cells. By silencing PSMA5, cancer cells undergo apoptosis and are inhibited in their proliferation. In addition, there is some evidence that bortezomib may be used to treat solid tumors, but monotherapy is not efficient, increasing the risk of tumor drug resistance to the drug. A preliminary study of bortezomib resistance was conducted, showing that inhibiting PSMA5 slows the progression of bortezomib-resistant prostate cancer [16, 42, 43].

These findings suggest that the increased proteasome activity may result from the increase in proteasome units and may be significant in the development of tumor proteasome drugs. At present, there are two generations of proteasome inhibitors, the first generation is represented by bortezomib, and the second generation is represented by malizomib. The first-generation bortezomib has achieved good results in myeloma [44]. Research is also being carried out to apply it to other types of tumors. For example, a phase II trial investigated its use in glioblastoma, yielding a five-year survival rate of 30%. A major disadvantage of first-generation proteasome inhibitors is their poor penetration of the blood–brain barrier. The second-generation malizomi improves on this point and has strong selectivity [2, 5]. Therefore, a phase III trial investigated the application of the third-generation drug in glioblastoma. Unfortunately, the phase III study was not successful. We hypothesize that inhibit PSMA5 expression might enhance the tumor sensitivity to proteasome inhibitors treatment.

Our study identified PSMA5 as a significant protein in the pathogenesis of glioma. The findings indicate that PSMA5 is crucial in regulating cell growth, cell cycle progression, and immune cell infiltration. PSMA5 has the potential to serve as a prognostic biomarker for glioma. Nevertheless, additional research is imperative to elucidate the molecular mechanisms underlying PSMA5's role in glioma carcinogenesis, which could potentially inform the development of novel therapeutic strategies against glioma.

Conclusion

Our study confirmed PSMA5 overexpression in glioma samples from the CGGA and TCGA databases. Furthermore, the clinical and prognostic role of PSMA5 mRNA expression in glioma was investigated. However, the present study is still deficient and. further research employing additional cell lines and in vivo experiments should be performed in the future to validate these results. Notwithstanding these shortcomings, our study clearly provided evidence that PSMA5 was overexpressed in glioma tissues and cells, leading to a poor prognosis in glioma patients. Moreover, knockdown of PSMA5 by si-RNA inhibited specific cell proliferation and induced cell cycle arrest. This study revealed the effects of PSMA5 on glioma and its potential underlying mechanisms, suggesting its potential role as a biological target for glioma treatment.

Supplementary Information

Supplementary materials 1.

Supplementary materials 2.

Supplementary materials 3.

Supplementary materials 4.

Acknowledgements

All authors sincerely acknowledge the contributions from the TCGA, CGGA, GTEx databases and BioGRID.

Author contributions

Wei Liu and Bo Jia designed the study and performed analysis. Jiwei Wang and Jie Tang supervised research and provided critical advice on the study. Zan Wang and Chengcai Li collected data and developed the methodology. Wei Liu and Nanding Li wrote the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by the Natural Science Foundation of Hebei Province (No. H2023206403).

Data availability

All data generated or analyzed during this study are obtained from TCGA dataset (https://portal.gdc.cancer.gov/), CGGA dataset (http://cgga.org.cn/).

Declarations

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The collection of all human samples in this study was approved by ethics board of The First Hospital of Hebei Medical University (No. 20221107). Informed consent was obtained from all patients.

Consent for publications

All co-authors have given their consent for publication.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wei Liu and Bo Jia contributed equally to this work and should be considered co-first authors.
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