Molecular Carcinogenesis最新文献

{"title":"The Contradictory Effects of SPTLC1 on Clear Cell Renal Carcinoma Sensitivity to Sunitinib Mediated by Androgen Receptor.","authors":"Liqiong Liao, Zhixiong Zhang, Zhenhua Li, Daqiang Wei, Yanni Xie, Haodong Zeng, Hongyang Zhao, Yuhao Zhou, Di Gu, Xiaolu Duan","doi":"10.1002/mc.70023","DOIUrl":"10.1002/mc.70023","url":null,"abstract":"<p><p>Serine palmitoyltransferase long chain-1 (SPTLC1) is a key enzyme in ceramide synthesis, previously identified as a suppressor of tumorigenesis in clear cell renal carcinoma (ccRCC). Although elevated levels of very long-chain ceramides are associated with the canonical multidrug resistance in ccRCC, the specific role of SPTLC1 in modulating the sensitivity of ccRCC to sunitinib remains unclear. In this study, we found that SPTLC1 overexpression could enhance the sensitivities of 786-O and OSRC-2 cells to sunitinib via downregulating CerS2 expression and long-chain ceramide levels. In contrast, SPTLC1 upregulated CerS2 expression and long-chain ceramide levels in A498 cells, yet without a significant impact on its sensitivity to sunitinib. In addition, overexpression of CerS2 significantly attenuated SPTLC1-enhanced sensitivities of 786-O and OSRC-2 cells to sunitinib, whereas CerS2 knockdown obviously enhanced the sensitivity of A498 cells to sunitinib. Moreover, androgen receptor (AR) expression was significantly decreased in SPTLC1-overexpressed 786-O cells and forced AR expression could obviously attenuate the downregulation of CerS2 expression induced by SPTLC1 in 786-O cells, whereas opposite results were observed in A498 cells, suggesting that the contradictory effects of SPTLC1 on CerS2 expression were modulated by AR. Taken together, our results demonstrated that the contradictory effects of SPTLC1 on clear cell renal carcinoma sensitivity to sunitinib were caused by AR-mediated CerS2 expression, thus revealing a novel role and mechanism of SPTLC1 in the regulation of ccRCC sensitivity to sunitinib.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1778-1791"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Influence of TNFSF15 Genetic Variants and Expression Levels on Disease Progression in Patients With Hepatocellular Carcinoma.","authors":"Kuan-Chun Hsueh, Yi-Hsien Hsieh, Shih-Chi Su, Edie-Rosmin Wu, Lun-Ching Chang, Shun-Fa Yang, Hsiang-Lin Lee","doi":"10.1002/mc.70026","DOIUrl":"10.1002/mc.70026","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), whose complex etiology involves a genetic component, is a global public health burden. Tumor necrosis factor superfamily member 15 (TNFSF15) is a T lymphocyte-costimulatory cytokine known to modulate angiogenesis and inflammation, implicating its potential role in cancer development. In this study, we attempted to explore the influence of TNFSF15 gene variations on the risk for HCC. In total, 408 HCC patients and 1190 noncancer controls were enrolled, and allelic distributions of TNFSF15 gene (rs3810936, rs6478108, and rs6478109) were analyzed using a TaqMan allelic discrimination assay. After adjustment for the putative confounding factors, none of these three SNPs was associated with the development of HCC. While assessing the clinicopathological parameters, we demonstrated that patients carrying at least one minor allele of rs6478108 (T) or rs6478109 (G) were less prone to develop distant metastasis (rs6478108, TC + TT vs. CC, OR, 0.414; 95% CI, 0.185-0.924, p = 0.027) (rs6478109, GA + GG vs. AA, OR, 0.397; 95% CI, 0.178-0.888; p = 0.021) as compared with patients who are homozygous for the major allele. In addition, preliminary exploration of public datasets exhibited that rs6478108 and rs6478109 affected TNFSF15 gene expression to various degrees in the liver tissues and whole blood samples. Moreover, gene silencing experiments revealed that elevated TNFSF15 levels are essential for promoting cell migration in HCC. Our results indicate gender-specific association of TNFSF15 gene polymorphisms with the metastatic potential of HCC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1751-1762"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnane X Receptor Activation Induces Ferroptosis Resistance Through Upregulation of FSP1.","authors":"Yingying Shang, Qi Yao, Ya Tan, Ruipeng Bian, Yanni Ma, Yuanze Zhou, Rong Mu, Nahua Xu, Yanyun Shi, Nan Lu, Lin Liu, Jieping Chen, Shuangnian Xu, Hui Li","doi":"10.1002/mc.70016","DOIUrl":"10.1002/mc.70016","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of programmed cell death, is emerging as a novel approach to tackling cancer. Cancer cells require large amounts of iron for their rapid growth, making them intrinsically vulnerable to ferroptosis. However, cancer cells have developed several important antioxidant pathways to counteract ferroptosis. One of these key pathways is the FSP1/CoQH2 pathway. In this study, we reveal a new regulatory mechanism of FSP1 involving the Pregnane X Receptor (PXR). Activation of PXR by rifaximin and rifampicin suppresses ferroptosis in a variety of cancer cells from different origins. The protective effect of rifaximin and rifampicin is lost in PXR knockout cells or in the presence of PXR inhibitor, validating the role of PXR in mediating the effects of these drugs. Additionally, rifaximin and rifampicin decrease lipid peroxidation and ferrous iron accumulation during ferroptosis induction, effects that are reversed in PXR knockout cells. Mechanistically, rifaximin and rifampicin induce the expression of FSP1 in a PXR-dependent manner, as they fail to induce FSP1 in PXR knockout cells. Furthermore, the ferroptosis protection effect of rifaximin and rifampicin is significantly compromised in FSP1 knockout cells or in the presence of the FSP1 inhibitor iFSP1. Importantly, we demonstrated that the PXR inhibitor pimecrolimus showed synergy with ferroptosis inducer sulfasalazine to repress tumor growth in vivo. Together, these findings provide evidence supporting an anti-ferroptosis role of PXR through the upregulation of FSP1 expression.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1620-1637"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYEOV Facilitates the Progression of Bladder Cancer by Upregulating MMP9 Via the TGF-β-H3K4me3 Epigenetic Axis.","authors":"Jianang Chen, Menjun Hu, Peizhen Wang, Rixu Lin, Shengwei Du, Xingan Chen, Wen Li, Guorong Chen, Hanbin Chen","doi":"10.1002/mc.70001","DOIUrl":"10.1002/mc.70001","url":null,"abstract":"<p><p>Bladder cancer (BC) represents the second most prevalent malignant tumor within the urinary system. Its high rates of recurrence and metastasis contribute to an unfavorable prognosis. The myeloma overexpressed gene (MYEOV) has been associated with the progression of various cancers. However, the specific role and underlying mechanisms of MYEOV in BC progression remain to be elucidated. Our research demonstrates that MYEOV is significantly upregulated in BC and correlates with poor clinical outcomes. Reducing or overexpressing MYEOV can inhibit or promote the proliferation and invasive ability of BC. Mechanistically, MYEOV activates the TGF-β-H3K4me3 signaling pathway to directly modulate MMP9 promoter activity through epigenetic modifications, thereby enhancing MMP9 expression. Notably, the effects of MYEOV knockdown or overexpression on BC proliferation and invasion can be counteracted by restoring MMP9 expression. Furthermore, NSUN2 modulates the stability of MYEOV mRNA via m5C methylation, leading to its increased expression in BC. Collectively, our findings elucidate the role of MYEOV in facilitating BC progression through the regulation of MMP9 in vitro. In conclusion, our findings identified that MYEOV is a novel target in the development of bladder cancer and offer new insights into potential therapeutic strategies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1708-1723"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Growth and Survival of Head and Neck Cancer Cells by Silibinin Involves the Down-Regulation of Erk1/2, AKT and STAT3 Signaling.","authors":"Navneendra Singh, Mansoor Ali, Priyanka Biswal, Aishwarya Jaiswal, Deepali Mishra, Rajesh Agarwal, Rana Zaidi, Rana P Singh","doi":"10.1002/mc.70022","DOIUrl":"10.1002/mc.70022","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and fatal cancers in India. Silibinin, a naturally occurring small molecule from milk thistle (Silybum marianum), is gaining attention as a potent anticancer agent against various cancers; however, its impact on HNSCC and the associated molecular mechanisms are largely unknown. We checked the effect of silibinin on proliferation, cell viability, and DNA damage in HNSCC cells, and employed immunoblotting to detect the underlined molecular mechanism. Also, we validated silibinin's anticancer efficacy and associated molecular changes in the xenograft mouse model. Silibinin inhibited cell proliferation and viability in HNSCC cells, and enhanced G1-S phase arrest by increasing p53 expression and inhibiting p27^Kip1, p21^Cip1, Cyclin D1-CDK4/6, and Cyclin E-CDK2 complexes. Silibinin-induced DNA damage and apoptosis in HNSCC cells were evidenced by comet assay, expression of p-H2AX, Bax, Bcl-2, and cleavage of caspase 3 and PARP proteins. Moreover, silibinin also impaired DNA repair pathways, ATM-Chk2, ATR-Chk1, DNA-PK, Ku70/80 and Rad51, and activated JNK contributing to DNA damage. The strong inhibition of EGFR-mediated Erk1/2, AKT and STAT3 signaling by silibinin was identified. Silibinin augmented PD98059 and LY294002-induced cell death and inhibition of pSTAT3. Silibinin inhibited Cal33 tumor growth in athymic mice model without any adverse effects. Our study revealed anticancer efficacy of silibinin in suppressing cell viability and proliferation, promoting DNA damage, apoptosis and cell cycle arrest in HNSCC. Further, oral silibinin inhibited Cal33 tumor xenograft growth. Hence, silibinin could have promising therapeutic efficacy for HNSCC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1735-1750"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monocarboxylate Transporter-1 Is Dispensable for Hepatocellular Carcinoma Development.","authors":"Shaimaa A Gad, Bryan Bridgeman, Kyle Boedeker, Xianzhong Ding, Wei Qiu","doi":"10.1002/mc.70021","DOIUrl":"10.1002/mc.70021","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the deadliest liver disease. It is imperative to understand the underlying molecular mechanisms involved in the development of HCC. Monocarboxylate transporter-1 (MCT1) is a proton-coupled protein that facilitates the bidirectional transport of monocarboxylates, such as lactate and pyruvate, across the plasma membrane to maintain the cellular metabolism and energy supply. MCT1 was found to be upregulated in human HCC specimens, and its inhibition reduced xenograft tumor growth. However, the role of MCT1 in HCC remains to be further investigated using immune-competent in vivo models. To better understand the role of MCT1 in HCC, we established liver-specific MCT1 knockout mice. We found that deletion of MCT1 in liver cells did not affect morphology, proliferation, or apoptosis. DEN/CCl4 model, where a single injection of DEN is followed by repeated injections of CCl4, was used to induce HCC in mice. Intriguingly, we found that liver-specific knockout of MCT1 was not sufficient to reduce the size or count of DEN/CCl4-induced liver tumors. In addition, we used immunohistochemical staining to evaluate the expression of Ki67, collagen A1, and myeloperoxidase, and we found that MCT1 knockout was not able to hinder the proliferation, fibrosis, and inflammation in the DEN/CCl4-induced HCC tumors. In conclusion, MCT1 is dispensable for HCC development, and its deletion was insufficient to alleviate the phenotypic repercussions of HCC tumors in the DEN/CCl4-induced HCC model.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1724-1734"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12451418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Withaferin A Exerts Cytotoxicity in Single/Multidrug-Resistant Gastric and Ovarian Cancer Cells and Tumor Xenografts Through the AKT-NF-κB-STAT3-Survivin Axis.","authors":"Priti S Shenoy, Shubhankar Dash, Diksha Joshi, Bharat Rekhi, Vikram Gota, Pritha Ray","doi":"10.1002/mc.70043","DOIUrl":"https://doi.org/10.1002/mc.70043","url":null,"abstract":"<p><p>Resistance to primary chemotherapeutics poses a significant challenge in treating solid tumors. The majority of the second-line chemo and targeted therapeutics act moderately/less effectively in drug-resistant tumors owing to the multicausal nature of drug resistance. Therefore, a single agent with pleiotropic effects would be beneficial in combating this adversity. Withania somnifera exhibits multifunctional anticancer properties, but its role in overcoming chemoresistance remains poorly understood. We evaluated the cytotoxic effect of Ashwamax^TM-W. somnifera (WS)-extract and Withaferin A (WFA), in intrinsically resistant (KATO-III and SKOV3) and acquired chemoresistant gastric (AGS^5FU) and ovarian (A2780^LR) cancer cellular models. We examined their impact on autophagy and apoptosis pathways and elucidated the underlying molecular mechanism. In vivo efficacy of WFA on cisplatin-paclitaxel-resistant epithelial ovarian cancer (EOC) xenografts was assessed using noninvasive optical imaging. Mechanistically, WFA is more proficient in targeting chemoresistant cells than Ashwamax^TM-WS extract and activates apoptosis by overriding the AKT-NF-κB-STAT3-survivin axis. Preclinical imaging revealed dose-dependent tumor regression (during and after treatment) in platinum-taxol-resistant EOC xenografts that were unresponsive to cisplatin challenge. WFA, at 3 mg kg^-1 dosage, reduced tumor volume by 4.7-fold compared to controls, with sustained antitumor effects persisting after treatment cessation. WFA effectively targets the AKT-NF-κB-STAT3-survivin axis to overcome single and multidrug resistance in gastric and epithelial ovarian cancers, presenting a promising therapeutic alternative for chemoresistant malignancies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POU4F1 Promotes the Primary Resistance of Melanoma to Anti-PD-1 Therapy by Regulating Glycolysis Through METTL1-Mediated m7G Methylation of PKM2.","authors":"Lin Liu, Xiaokang Li, Xinhong Hu, Da Zhai, Tianyu Cao, Ling Liu","doi":"10.1002/mc.70049","DOIUrl":"https://doi.org/10.1002/mc.70049","url":null,"abstract":"<p><p>Melanoma, a highly malignant tumor originating from melanocytes, has seen a significant increase in global incidence, particularly among the elderly. Anti-PD-1 monoclonal antibodies, which activate the immune system to attack cancer cells by blocking the PD-1/PD-L1 signaling pathway, have improved survival rates but face challenges such as innate resistance. This study enrolls 37 melanoma patients and 7 benign nevus patients, with tissue samples collected for analysis. RT-qPCR and Western blot are used to quantify the expression of the target protein. Flow cytometry is utilized to analyze immune subsets in tumors. Glucose uptake, lactate production, and ATP level are assessed by commercial kits. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) are measured using a Seahorse XF Analyzer. RNA Bisulfite Sequencing is performed to quantify pyruvate kinase M2 (PKM2) m7G methylation level, MeRIP-qPCR is conducted to validate the m7G methylation level of PKM2, and RIP assay is conducted to confirm POU4F1-METTL1 interaction. The results show that POU Class 4 Homeobox 1 (POU4F1) is upregulated in melanoma tissues compared to benign nevi. Anti-PD-1 treatment effectively reduces POU4F1 expression in sensitive B16-F10-M tumors and has no significant effect on resistant B16-F10-R tumors. POU4F1 overexpression induces profound metabolic alterations, including increased lactate production, glucose uptake, and ECAR, while suppressing OCR in B16-F10-M cells. POU4F1 overexpression also reduces the infiltration of CD8⁺ T cells, M1-macrophages, and NK cells, while increasing Treg and M2-macrophage populations in B16-F10-M cells. Importantly, 3-Bromopyruvate (a glycolysis inhibitor) reverses these effects. Mechanistically, POU4F1 upregulates METTL1 expression and increases m7G methylation of PKM2 mRNA. Besides, there is an interaction between POU4F1 and METTL1. METTL1 is also overexpressed in melanoma tissues compared to benign nevi. In conclusion, POU4F1 drives anti-PD-1 resistance in melanoma by enhancing glycolysis via METTL1-mediated m7G methylation of PKM2. Targeting the POU4F1-METTL1-PKM2 axis may improve melanoma immunotherapy outcomes.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Integrative Drug-Induced Transcriptomic Analysis Identifies Novel MYC Antagonists and Potential Synergistic Drug Combinations.","authors":"Anthony Aceto, Yue Wang, Da Yang","doi":"10.1002/mc.70044","DOIUrl":"https://doi.org/10.1002/mc.70044","url":null,"abstract":"<p><p>MYC is among the most frequently dysregulated oncogenes in human cancer, yet its direct targeting remains a significant challenge. Here, we present an in-silico integrative screening approach to identify compounds and combinations that can block MYC's oncogenic function by specifically disrupting its transcriptional regulatory function. Using a doxycycline (DOX)-inducible model, we established a MYC loss-of-function (LOF) gene signature that specifically captures the molecular consequences corresponding to the loss of MYC's ability in transcriptional regulation. By integrating large-scale post-perturbation transcriptomic profiling from the CMAP database, we screened over 8300 drug-induced profiles and identified 70 recurrent compounds that are predicted to antagonize MYC's transcriptional programs. To further enhance their therapeutic potential, we also developed an orthogonality analysis to pinpoint synergistic drug combinations that suppress MYC activity more effectively than single agents. Our scalable framework enables a rational and systematic identification of compounds with potential to antagonize MYC's oncogenic function by disrupting its transcriptional regulatory ability without necessarily decreasing its abundance. Our approach provides new insights on utilizing existing anticancer drugs to indirectly target MYC in MYC-driven cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA m⁵C Modifications in the Development and Prognosis of Muscle-Invasive Bladder Cancer.","authors":"Lili Zhang, Liying Zhou, Wenrui Xu, Pengjie Wu, Wen Chen, Hexin Li, Gaoyuan Sun, Siyuan Xu, Xiaokun Tang, Lipin Liu, Yaqun Zhang, Qiuzi Zhong","doi":"10.1002/mc.70042","DOIUrl":"https://doi.org/10.1002/mc.70042","url":null,"abstract":"<p><p>The m⁵C RNA modifications have been implicated in the pathogenesis of urothelial carcinoma and hold potential as prognostic biomarkers for muscle-invasive bladder cancer (MIBC) patients. In this study, we developed an MIBC-risk model by integrating m⁵C modification-related genes and differentially expressed genes using Nanopore sequencing and a machine learning approach. Compared to our previous research, we observed that m⁵C modifications are more functional, with the most enriched regions being the 3'UTR and exons. Our analysis revealed differential m⁵C methylation sites in several well-characterized cancer-related genes, including BMI1, PTEN, MALAT1, FADD, STAT5A, BIRC6, FOXO3, CCNG1, PAK2, UBE2L3, SMARCB1, and TUG1. Functional enrichment analysis demonstrated significant involvement of these genes in key oncogenic pathways, particularly DNA damage response, double-strand break repair, p53 signaling, MAPK cascade, NF-κB signaling, and cell proliferation/migration pathways. Unlike models based on single factors, the combination of m⁵C modification-related genes and differentially expressed genes resulted in a more effective classification model. This approach yielded an optimized 11-gene prognostic signature comprising GGA1, NUMBL, ECHDC2, NLRC5, EIF2D, GJA1, XPC, DAZAP2, C6orf120, WDR45, and CES1, which demonstrated superior predictive performance in TCGA MIBC patients. These findings establish m⁵C RNA modification patterns as promising molecular signatures for MIBC prognosis and potential therapeutic targets.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}