Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献

{"title":"A novel mechanism in driving non-small cell lung cancer progression: The METTL3/FOXA1/PTK2 cascade","authors":"Xuelin Zhang ,&nbsp;Yizhao Chen ,&nbsp;Lingjie Wang ,&nbsp;Qingyue Lin ,&nbsp;Tingjian Li ,&nbsp;Chunya He","doi":"10.1016/j.mrfmmm.2025.111911","DOIUrl":"10.1016/j.mrfmmm.2025.111911","url":null,"abstract":"<div><h3>Background</h3><div>Dysregulation of m6A modification has significant implications in human carcinogenesis. METTL3, a crucial m6A writer, acts as an oncogenic driver in non-small cell lung cancer (NSCLC). Here, we explored its mechanisms in driving NSCLC development.</div></div><div><h3>Methods</h3><div>Cell sphere formation, invasion, apoptosis, and proliferation were detected by sphere formation, transwell, flow cytometry, and MTT assays, respectively. Cell glycolysis was evaluated by measuring glucose consumption, lactate production, and ATP/ADP ratio. RIP, methylated RIP (MeRIP), and mRNA stability assays were used to analyze the METTL3/FOXA1 relationship. Luciferase assay and ChIP experiment were used for the evaluation of the FOXA1/PTK2 relationship. Xenograft studies were used to test the role <em>in vivo</em>.</div></div><div><h3>Results</h3><div>METTL3 was upregulated in NSCLC, and its inhibition diminished the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Mechanistically, METTL3 depletion caused a reduction in FOXA1 expression through the m6A modification mechanism. FOXA1 transcriptionally controlled PTK2 expression. FOXA1 upregulation reversed the effects of METTL3 inhibition on the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Moreover, FOXA1 increase attenuated the impact of METTL3 inhibition on the <em>in vivo</em> growth of A549 subcutaneous xenografts. Additionally, increased PTK2 expression counteracted the effects of FOXA1 reduction on the malignant phenotypes of H1299 and A549 cells.</div></div><div><h3>Conclusion</h3><div>Our finding elucidates a novel mechanism for METTL3’s oncogenic activity in NSCLC, where METTL3 upregulates FOXA1 and thus activates PTK2 transcription. Blocking this cascade may be effective for combating NSCLC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111911"},"PeriodicalIF":1.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14-mediated m6A modification of ETV4 inhibits tumor development in colorectal cancer","authors":"Xiaofeng Liao,&nbsp;Tao Hu","doi":"10.1016/j.mrfmmm.2025.111910","DOIUrl":"10.1016/j.mrfmmm.2025.111910","url":null,"abstract":"<div><h3>Background</h3><div>Many m6A methyltransferases have been identified to regulate colorectal cancer (CRC) progression. METTL14 has been confirmed to play a negative role in CRC process, but the molecular mechanism of METTL14 in regulating CRC progression needs to be further elucidated.</div></div><div><h3>Methods</h3><div>The levels of METTL14, YTHDF2 and ETS translocation variant 4 (ETV4) were examined by qRT-PCR and western blot. Cell proliferation and apoptosis were determined by colony formation assay and flow cytometry. Cell glycolysis was assessed by detecting corresponding indicators. Cell ferroptosis was evaluated via measuring SOD, MDA, GSH, ROS and Fe^2 + levels. The interaction between ETV4 and METTL14 or m6A readers was confirmed by RIP assay and RNA pull-down assay. Animal experiments were performed to confirm METTL14 roles <em>in vivo</em>.</div></div><div><h3>Results</h3><div>METTL14 was downregulated in CRC tissues and cells, which overexpression inhibited proliferation and glycolysis, as well as promoted apoptosis and ferroptosis in CRC cells. METTL14 reduced the mRNA stability of ETV4 and inhibited ETV4 protein expression through m6A modification. m6A reader YTHDF2 could recognize m6A-methylated ETV4. The downregulation of ETV4 by METTL14 leads to increased apoptosis and ferroptosis in CRC cells, suggesting a critical role in tumor suppression. Moreover, METTL14 inhibited CRC tumorigenesis <em>in vivo</em> via reducing ETV4 expression.</div></div><div><h3>Conclusion</h3><div>METTL14 accelerated CRC cell apoptosis and ferroptosis via downregulating ETV4 in m6A-dependent manner, providing a molecular target for CRC treatment.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111910"},"PeriodicalIF":1.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP7 accelerates colorectal cancer progression by up-regulating MYO6 through deubiquitination","authors":"Ming Jiang ,&nbsp;Chong Xiong","doi":"10.1016/j.mrfmmm.2025.111908","DOIUrl":"10.1016/j.mrfmmm.2025.111908","url":null,"abstract":"<div><h3>Background</h3><div>Ubiquitin-specific protease 7 (USP7) is one of deubiquitinases and has been reported to regulate cancer cell biological processes through removing ubiquitin modifications from protein substrates. Myosins of class VI (MYO6) is shown to be highly expressed in many of cancers, and is associated with tumor progression in several cancers by affecting cell survival. Moreover, USP7 and MYO6 have been revealed to be involved in colorectal cancer (CRC) progression. Here, we aimed to investigate the intricate interplay between MYO6 and USP7 in CRC, and whether their interaction was associated with deubiquitination.</div></div><div><h3>Methods</h3><div>Quantitative real-time PCR and western blot were used to for mRNA and protein detection. Functional analyses were conducted using Cell Counting Kit-8, 5-ethynyl-2-deoxy-uridine, flow cytometry, wound healing and transwell assays in vitro, and murine xenograft models in vivo. M2 macrophage polarization was determined with CD206 antibody using flow cytometry. The protein interaction between MYO6 and USP7 was determined by chromatin immunoprecipitation assay. The deubiquitination effect of USP7 was validated by cellular ubiquitination and immunoprecipitation assay.</div></div><div><h3>Results</h3><div>CRC tissues and cells showed high expression of MYO6. Functionally, silencing of MYO6 suppressed CRC cell proliferation, migration, invasion, angiogenesis, induced cell apoptosis and negatively affected macrophage M2 polarization in vitro, and impeded CRC growth in vivo. For a mechanism analysis, USP7 could stabilize and up-regulate MYO6 expression by inducing MYO6 deubiquitination. USP7 was also highly expressed in CRC, USP7 silencing repressed CRC cell malignant phenotypes and reduced macrophage M2 polarization, while these effects were reversed by MYO6 overexpression.</div></div><div><h3>Conclusion</h3><div>MYO6 promoted CRC cell tumorigenesis and macrophage M2 polarization, and the mechanism was associated with USP7-induced MYO6 deubiquitination. These results suggested new targets for the development of epigenetic-based therapy in CRC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111908"},"PeriodicalIF":1.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico report on five high-risk protein C pathogenic variants: G403R, P405S, S421N, C238S, and I243T","authors":"Daniela Hristov ,&nbsp;Done Stojanov","doi":"10.1016/j.mrfmmm.2025.111907","DOIUrl":"10.1016/j.mrfmmm.2025.111907","url":null,"abstract":"<div><div>In this study, we propose reclassification of 5 out of 16 <em>PROC</em> VUS (variants of uncertain significance): C238S, I243T, G403R, P405S, and S421N, as pathogenic variants, associated with thrombophilia due to <em>PROC</em> deficiency. The obtained results are based on in silico analysis, which enables a detailed assessment of variants’ impact, despite limited clinical evidence. In particular, the G403R substitution, next to the S402-active site, is expected to reduce the flexibility of the local coil domain, affecting the catalytic activity of serine protease. The P405S substitution may imply B-factor gain (P = 0.24; p-value=0.040). On the other hand, the S421N variant causes phosphorylation site disruption at S421, which serves as a target for CK2 phosphorylation. C238S substitution alters metal binding, while the I243T variant may alter transmembrane properties (P = 0.27, P-value=0.00071). All five <em>PROC</em> variants hold promise as diagnostic markers for protein C deficiency and may also serve as potential drug targets for therapeutic intervention.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111907"},"PeriodicalIF":1.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT6 regulates the HIPK2/P53 pathway to reduce oxidative stress and apoptosis to attenuate vancomycin-induced nephrotoxicity","authors":"Xiuying Feng ,&nbsp;Yunhui Liu ,&nbsp;Lei Su ,&nbsp;Luyang Xu","doi":"10.1016/j.mrfmmm.2024.111897","DOIUrl":"10.1016/j.mrfmmm.2024.111897","url":null,"abstract":"<div><div>SIRT6 is known to play a protective role in several kidney diseases; however, its role in vancomycin-induced renal injury remains unclear. This study aims to confirm the role and related mechanisms of SIRT6 in vancomycin-induced renal injury. To develop a kidney damage model, mice were given vancomycin injections for seven days. Additionally, an in vivo transfection with a SIRT6 overexpression plasmid was performed. PCR and Western blot analyses were used to assess the SIRT6 mRNA and protein expression levels in renal tissue. HE staining was performed to evaluate renal tissue damage, while Scr and BUN were measured using specialized kits. Renal tissue apoptotic cells were labeled using a TUNEL kit, and the levels of the antioxidant enzymes SOD and GSH were measured using appropriate kits. Western blot was used to identify HIPK2, p-p53, and p53 protein expression in the renal tissue. The results reveal that SIRT6 is expressed at markedly low levels in renal tissue. Furthermore, mice administered vancomycin exhibited a significant increase in Scr and BUN levels, indicating impaired renal function. Histological examination through HE staining demonstrated considerable damage to the renal tissue of the vancomycin group. Additionally, the renal tissue of the mice in the vancomycin group displayed reduced levels of the antioxidant enzymes SOD and GSH, an increased number of TUNEL-positive cells, and significantly elevated levels of HIPK2 and p-p53 protein expression. Moreover, the mice transfected with SIRT6 exhibited significant improvements in previously described symptoms. These findings imply that the inhibition of HIPK2/p53 by SIRT6 may represent a promising therapeutic strategy for alleviating vancomycin-induced nephrotoxicity.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111897"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143178151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cancer-cell mitochondria using Tigecycline improves radiotherapy response in colorectal cancer cell line","authors":"Sepideh Hassanpour Khodaei ,&nbsp;Shahnaz Sabetkam ,&nbsp;Zeinab Mazloumi ,&nbsp;Khadijeh Dizaji Asl ,&nbsp;Ali Rafat","doi":"10.1016/j.mrfmmm.2025.111905","DOIUrl":"10.1016/j.mrfmmm.2025.111905","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC) is the third most common cancer worldwide and causes more than 50,000 deaths in the United States each year. Due to the limited therapeutic options and poor prognosis in CRC, extensive research and development of novel therapeutic methods is essential. In this regard, the presence of cancer stem cells with unlimited division ability is the main reason for the therapeutic resistance in CRC. Tigecycline is a pharmacological mitochondria inhibitor and blocks mitochondria-related cell proliferation in cancer cells. This study investigated the effects of Tigecycline combined with radiotherapy on CRC cell apoptosis.</div></div><div><h3>Methods</h3><div>Human colorectal cancer cells (HCT-116) were treated with Tigecycline, and cell viability was measured with MTT assay. In the next step, the cells were exposed to radiation using a Siemens Primus 6 MV linear accelerator at radiation dose of 400 cGy. Finally, we evaluated cancer cell apoptosis, caspase-3 activity and apoptotic-related genes expression with AnnexinV/PI, flowcytometry and gene expression, respectively.</div></div><div><h3>Results</h3><div>The MTT assay revealed an IC50 value of 93 μM for Tigecycline after 48 hours. Mitochondria inhibition, at its IC50 value, sensitizes colorectal cancer cells to radiotherapy. Compared to monotherapy, the combination therapy increased the number of apoptotic cells and caspase-3 activity, up-regulated pro-apoptotic genes, and down-regulated anti-apoptotic genes.</div></div><div><h3>Conclusion</h3><div>In conclusion, our data suggests that targeting mitochondria may represent a clinically relevant approach to enhance the sensitivity of colorectal cancer cells to therapy. These findings could provide new insights into cancer therapy and might be used as a novel method to improve the current state of CRC therapy.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111905"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complex development of psoralen-interstrand crosslink resistance in Escherichia coli requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators","authors":"Travis K. Worley ,&nbsp;Ayah H. Asal,&nbsp;Lo Cooper,&nbsp;Charmain T. Courcelle,&nbsp;Justin Courcelle","doi":"10.1016/j.mrfmmm.2025.111898","DOIUrl":"10.1016/j.mrfmmm.2025.111898","url":null,"abstract":"<div><div>Crosslinking agents, such as psoralen and UVA radiation, can be effectively used as antimicrobials and for treating several dysplastic conditions in humans, including some cancers. Yet, both cancer cells and bacteria can become resistant to these compounds, making it important to understand how resistance develops. Recently, several mutants were isolated that developed high levels of resistance to these compounds through upregulation of components of the AcrAB-TolC efflux pump. Here, we characterized these mutants and found that resistance specifically requires inactivating mutations of the <em>acrR</em> transcriptional repressor which also retain the <em>marbox</em> sequence found within this coding region. In addition, the presence of any one of three global regulators, MarA, SoxS, or Rob, is necessary and sufficient to bind to the <em>marbox</em> sequence and activate resistance. Notably, although psoralen is a substrate for the efflux pump, these regulators are not naturally responsive to this stress as neither psoralen, UVA, nor crosslink induction upregulates <em>acrAB</em> expression in the absence of mutation.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111898"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143178152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CUEDC1 promotes the growth, migration, epithelial-mesenchymal transition and inhibits apoptosis of hepatocellular carcinoma cells via the TGF-β/Smad signaling pathway","authors":"Angjian Zhou ,&nbsp;Fuyu Chen ,&nbsp;Zhongchao Chen","doi":"10.1016/j.mrfmmm.2025.111900","DOIUrl":"10.1016/j.mrfmmm.2025.111900","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the precise molecular by which CUEDC1, a 42 kDa protein containing a CUE domain located on chromosome 17q22, contributes to liver cancer metastasis.</div></div><div><h3>Method</h3><div>CUEDC1 protein expression levels were determined in liver cancer cells using Western blot analysis. The expression of CUEDC1 in these cells was silenced through siRNA transfection Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Cell invasion and migration capabilities were evaluated using Transwell assays. The expression of transforming growth factor-beta (TGF-β)/ small mother against decapentaplegic (Smad) pathway, N-cadherin, alpha -smooth muscle actin (α-SMA), and E-cadherin was detected using Western blot.</div></div><div><h3>Result</h3><div>CUEDC1 expression was found to be elevated in liver cancer cells. Knockdown of CUEDC1 reduced the expression of TGF-β, p-Smad2, and p-Smad3, key components of the TGF-β/Smad pathway. Additionally, CUEDC1 knockdown significantly decreased cell survival, migration, invasion, and the EMT process in liver cancer cells.</div></div><div><h3>Conclusion</h3><div>CUEDC1 knockdown markedly reduces EMT and liver cancer cell metastasis by suppressing the TGF-β/Smad signaling pathway.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111900"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma","authors":"Di Zhang,&nbsp;Xinwu Zhang,&nbsp;Shuai Chang,&nbsp;Yao Zhao,&nbsp;Li Zhang","doi":"10.1016/j.mrfmmm.2025.111902","DOIUrl":"10.1016/j.mrfmmm.2025.111902","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.</div></div><div><h3>Methods</h3><div>RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis <em>in vivo</em>.</div></div><div><h3>Results</h3><div>High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. <em>In vivo</em>, USP19 knockdown controlled HCC growth by modulating c-Myc.</div></div><div><h3>Conclusion</h3><div>E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111902"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications","authors":"Manishankar Kumar ,&nbsp;Arun Kumar ,&nbsp;Abhinav Srivastav ,&nbsp;Ashok Ghosh ,&nbsp;Dhruv Kumar","doi":"10.1016/j.mrfmmm.2024.111896","DOIUrl":"10.1016/j.mrfmmm.2024.111896","url":null,"abstract":"<div><div>Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111896"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}