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

{"title":"E2F1 promotes LIHC malignant phenotype via NEK2-mediated Wnt/β-catenin and Notch activation and EMT","authors":"Lingju Hong,&nbsp;Shaoying Ke,&nbsp;Shaoze Lin,&nbsp;Gongle Wu,&nbsp;Congren Wang","doi":"10.1016/j.mrfmmm.2026.111935","DOIUrl":"10.1016/j.mrfmmm.2026.111935","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (LIHC) is the most common primary liver cancer, with high recurrence and metastasis rates, and its molecular mechanisms remain incompletely understood.</div></div><div><h3>Methods</h3><div>The cancer genome atlas (TCGA) database was used to obtain LIHC-related information. TNMplot, gene expression profiling interactive analysis (GEPIA), and kaplan-meier plotter were used for differential gene expression analysis, visualization, and assessing the relationship between genes and patient survival. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were used to detect gene and protein expression levels. Cell transfection was used for gene knockdown and overexpression. Transwell and wound healing assays were used to evaluate cell migration and invasion. The jaspar database was used to predict transcription factor-gene interactions. Chromatin immunoprecipitation (ChIP) and dual-luciferase assays were used to validate transcription factor-gene binding.</div></div><div><h3>Results</h3><div><em>Never in mitosis gene a related kinase 2</em> (<em>NEK2</em>) was highly expressed in LIHC, and its high expression potentially had a negative impact on patient survival. <em>NEK2</em> knockdown reduced the migration and invasion abilities of LIHC cells, decreased the expression of epithelial-mesenchymal transition (EMT) markers neural cadherin (N-cadherin) and vimentin, and increased epithelial cadherin (E-cadherin) expression, whereas <em>NEK2</em> overexpression showed the opposite effects. E2F transcription factor 1 (<em>E2F1</em>) was also highly expressed in LIHC and positively regulated <em>NEK2</em>, exhibiting similar regulatory effects on LIHC cells. Moreover, <em>NEK2</em> was positively correlated with Wnt/β-catenin marker catenin beta 1 (CTNNB1), as well as Notch signaling markers notch receptor 1 (NOTCH1), jagged canonical notch ligand 1 (JAG1), HES family BHLH transcription factor 1 (HES1), and HES-related family BHLH transcription factor with YRPW motif 1 (HEY1).</div></div><div><h3>Conclusion</h3><div>The <em>E2F1</em>/<em>NEK2</em> axis promotes the activation of Wnt/β-catenin and Notch signaling pathways and induces EMT to drive malignant behavior of LIHC cells.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111935"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147656871","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":"Deubiquitinase USP10 regulates angiotensin II-induced renal fibrosis by modulating the expression of TLR4","authors":"Rong Wang ,&nbsp;Yanjun Shen ,&nbsp;Jiaqi Shi ,&nbsp;Huaxing Huang ,&nbsp;Sujuan Feng ,&nbsp;Xingxing Fang ,&nbsp;Xiameng Gu ,&nbsp;Yang Yu","doi":"10.1016/j.mrfmmm.2026.111932","DOIUrl":"10.1016/j.mrfmmm.2026.111932","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic kidney disease (DKD) is one of the main causes of chronic kidney disease (CKD). There is evidence suggesting that the upregulation of Toll-like receptor 4 (TLR4) can exacerbate the progression of diabetic nephropathy. In addition, the expression of the deubiquitinating enzyme USP10 is upregulated in the kidney tissues of patients with CKD. However, the specific relationship between USP10 and TLR4 has not been clearly elucidated.</div></div><div><h3>Methods</h3><div>Human renal mesangial cells (HRMCs) were induced with angiotensin II (Ang II) to mimic the pathological features of renal fibrosis. The mRNA and protein levels of TLR4 and USP10 were monitored by RT-qPCR and western blot. Then, cell proliferation behavior was visualized by EdU. Meanwhile, the levels of ROS, GSH, MDA, SOD, IL-6, and TNF-α in HRMCs were measured with the corresponding kits. The UbiBrowser website was subsequently applied to predict TLR4 binding to USP10. Furthermore, the binding of USP10 to TLR4 and its deubiquitination modification of TLR4 were validated by IP, IB and, Co-IP techniques. The protein stability of TLR4 was examined in the presence of cycloheximide (CHX).</div></div><div><h3>Results</h3><div>TLR4 was highly expressed in DKD kidney tissues and AngII-induced HRMCs, and silencing TLR4 could effectively prevent the abnormal proliferation, oxidative stress, inflammation, and fibrosis process of HRMCs caused by AngII. Additionally, USP10 expression was upregulated in DKD kidney tissues and AngII-induced HRMCs, which mediated TLR4 deubiquitination to stabilize its protein expression. Most importantly, overexpression of TLR4 reversed the effect of USP10 silencing on AngII-induced HRMCs.</div></div><div><h3>Conclusion</h3><div>This study elucidated that USP10 facilitated the deubiquitination of TLR4 within AngII-stimulated HRMCs, thereby sustaining elevated levels of TLR4 protein. This mechanism not only incited aberrant proliferation of HRMCs but also triggered oxidative stress and inflammatory responses, ultimately expediting the progression of renal fibrosis.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111932"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483081","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":"Deciphering the structural and functional impact of interleukin-3 (IL-3) variants: Insights from site-directed mutagenesis, computational modeling, molecular dynamics simulations, and implications for anticancer therapies and immune regulation","authors":"Allah Rakha Yaseen ,&nbsp;Uzma Nisar ,&nbsp;Munir Ahmad ,&nbsp;Faiza Saleem ,&nbsp;Hafsa Amjad","doi":"10.1016/j.mrfmmm.2025.111927","DOIUrl":"10.1016/j.mrfmmm.2025.111927","url":null,"abstract":"<div><div>Interleukin-3 (IL-3) is a pivotal cytokine in immune regulation, making it a compelling target for therapeutic intervention in immune-related disorders. This study employs an integrative computational approach, combining site-directed mutagenesis, molecular dynamics simulations, and protein-protein docking, to systematically investigate the structural and functional consequences of IL-3 mutations. By mapping disease-associated variants and their mechanistic impact on IL-3 receptor (IL-3Rα) interactions, we uncover critical determinants of cytokine signaling and stability. Our findings reveal that mutations such as E41L, R127L, and W123E induce structural perturbations linked to disease phenotypes, underscoring their potential as therapeutic targets. Conversely, variants like H45R, D40A, and N124D exhibit altered receptor-binding affinities, presenting opportunities for rational drug design. Protein-protein docking further elucidates the molecular basis of IL-3Rα recognition, highlighting key residues that govern binding specificity. Notably, mutations affecting interface residues drive substantial changes in binding energetics, providing novel insights into IL-3-mediated signaling modulation. This study advances the understanding of IL-3 structural dynamics through a computational lens, offering a predictive framework for mutation-driven functional alterations. By integrating biophysical modeling with functional annotation, we establish a foundation for precision engineering of IL-3 variants with therapeutic potential. Despite the inherent limitations of <em>in silico</em> modeling, our approach provides preliminary computational insights into cytokine modulation and forms a foundation for future experimental validation aimed at exploring potential therapeutic avenues for IL-3-associated pathologies</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111927"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795712","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 active compound quercetin from Polygonum cuspidatum targets COL3A1 to enhance CD8⁺ T cell cytotoxicity in gastric cancer","authors":"Yunhai Wei ,&nbsp;Huancen Guo ,&nbsp;Wenjing Hu ,&nbsp;Yishi Xiao ,&nbsp;Jinyu Zhang ,&nbsp;Jingrui Cao ,&nbsp;Chu Shen ,&nbsp;Zhongxin Wu ,&nbsp;Lei Yin ,&nbsp;Yuhai Gao","doi":"10.1016/j.mrfmmm.2026.111937","DOIUrl":"10.1016/j.mrfmmm.2026.111937","url":null,"abstract":"<div><h3>Background</h3><div>Gastric cancer (GC) is a highly prevalent gastrointestinal malignancy with poor prognosis worldwide, and its initiation and progression are closely associated with tumor immune escape. <em>Polygonum cuspidatum</em>, a traditional Chinese medicine, exerts certain anti-tumor activity. However, its key active components and the underlying molecular mechanisms by which they regulate GC immune microenvironment remain to be systematically elucidated.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was performed based on the TCGA and TCMSP databases to screen potential targets of quercetin, an active component of <em>Polygonum cuspidatum</em>. Direct interactions between quercetin and key target proteins were verified by molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. CCK-8, colony formation, wound healing, Transwell, and flow cytometry were used to evaluate the effects of quercetin and COL3A1 expression on the proliferation, migration, invasion, and apoptosis of GC cells. A direct co-culture system of GC cells and CD8⁺ T cells was established, and the degree of exhaustion and cytotoxic function of CD8⁺ T cells were assessed by flow cytometry, ELISA, and LDH assay. Finally, a mouse allograft tumor model was constructed to verify the anti-tumor effect of quercetin <em>in vivo</em>.</div></div><div><h3>Results</h3><div>COL3A1 was identified as a core target gene of quercetin in GC and was highly expressed in GC cells. Quercetin could directly bind to COL3A1, significantly inhibit the proliferation, migration and invasion of GC cells, and promote apoptosis. Mechanistically, COL3A1 upregulated PD-L1 expression by activating the NF-κB signaling pathway, thereby attenuating the anti-tumor function of CD8⁺ T cells. Quercetin reversed COL3A1-mediated NF-κB activation and PD-L1 upregulation, restoring the cytotoxicity of CD8⁺ T cells against GC cells.</div></div><div><h3>Conclusion</h3><div>This study reveals the molecular mechanism by which quercetin directly targets COL3A1 and inhibits the COL3A1/NF-κB/PD-L1 axis, thereby alleviating CD8⁺ T cell exhaustion and enhancing anti-tumor immunity in GC. These findings provide a theoretical basis for the application of <em>Polygonum cuspidatum</em> and quercetin in GC immunotherapy, and suggest that COL3A1 may serve as a potential therapeutic target.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111937"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709792","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":"Maternal exposure to sucrose and maltodextrin alters metabolism and genotoxicity in mice offspring","authors":"Marina Lummertz Magenis ,&nbsp;Whayne Alves Alecrim ,&nbsp;Otávio Lúcio Possamai ,&nbsp;Isadora de Oliveira Monteiro ,&nbsp;Nicollas dos Santos da Silva ,&nbsp;Carolina Giassi Alano ,&nbsp;Adriani Paganini Damiani ,&nbsp;Helen Barbosa Vicente ,&nbsp;Isadora Luciano Machado ,&nbsp;Rafaela Cristina Silva de Almeida ,&nbsp;Isabela da Silva Lemos ,&nbsp;Emílio Luiz Streck ,&nbsp;Vanessa Moraes de Andrade","doi":"10.1016/j.mrfmmm.2026.111933","DOIUrl":"10.1016/j.mrfmmm.2026.111933","url":null,"abstract":"<div><div>Early metabolic events during the intrauterine period can increase susceptibility to chronic diseases in adulthood. Fetal and neonatal nutrition rich in sugars may lead to disorders such as obesity, insulin resistance, and diabetes. This study evaluated the effects of maltodextrin and sucrose intake in Swiss female mice treated during gestation and lactation, as well as in their offspring. Sixty-day-old mating pairs were used, receiving nutritional interventions (maltodextrin 10%/L, sucrose 10%/L, or water) during mating, gestation, and lactation (7, 21, and 21 days, respectively), totaling 49 days. Genetic (comet assay, micronucleus test) and biochemical (glycemia and electron transport chain) analyses were performed in dams and in offspring of both sexes at postnatal days (PND) 21 and 30. In dams, food intake and body weight were monitored, whereas in offspring, anthropometric parameters were assessed. Results showed that both carbohydrates increased fluid and calorie intake without affecting maternal body weight. Sucrose raised fasting glucose significantly. Comet assay revealed increased DNA damage after gestation and lactation, especially in the cortex for maltodextrin (p &lt; 0.05), with no changes in liver or hippocampus. The micronucleus test showed increased PCE micronuclei in the maltodextrin group (p &lt; 0.05). Complex I activity increased in the liver with both carbohydrates, while Complex II–III decreased with sucrose. In the cortex, both carbohydrates increased Complex II and reduced Complex IV; in the hippocampus, Complex I increased with both, and Complex IV increased with maltodextrin. In the offspring, sucrose-exposed males had greater body weight at 21 days, and females showed increased glycemia at 30 days. Overall, findings suggest that maltodextrin and sucrose intake during pregnancy and lactation can induce long-term metabolic and genetic alterations in mothers and offspring.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111933"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147448760","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":"2025-07-01","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":"Deciphering the molecular mechanism of YY1/HIF1A modulating ovarian cancer angiogenesis based on single-cell transcriptomics technology","authors":"Xiyun Quan ,&nbsp;Huimei Yi ,&nbsp;Meiyuan Huang,&nbsp;Dongliang Chen","doi":"10.1016/j.mrfmmm.2025.111916","DOIUrl":"10.1016/j.mrfmmm.2025.111916","url":null,"abstract":"<div><h3>Background</h3><div>Angiogenesis assumes an essential role in tumor development and is a fundamental condition for tumor growth. Yin Yang 1 (YY1) is highly expressed in various types of cancers and is a key player in tumor angiogenesis, but its role in ovarian cancer (OC) has not been fully elucidated. Therefore, this study will delve into the mechanism of YY1 in OC angiogenesis.</div></div><div><h3>Methods</h3><div>Based on single-cell transcriptomics data of OC tumor samples and adjacent samples downloaded from the GEO database, differentially expressed genes (DEGs) and related signaling pathways were screened and validated in OC cells. Furthermore, co-culture technology was applied to assess the impact of YY1 expression in OC cells on angiogenesis ability. The molecular mechanism of YY1 regulation of OC angiogenesis was explored through bioinformatics analysis combined with co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assays. Rescue experiments were designed, with results validated in qRT-PCR, angiogenesis assays, and Western blotting.</div></div><div><h3>Results</h3><div>Based on re-analysis of single-cell transcriptomics data from OC tumor samples and adjacent samples, we found that YY1 expression was significantly upregulated in OC cells, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that DEGs in YY1-positive tumor cells were significantly enriched in the HIF-1 signaling pathway. Moreover, <em>in vitro</em> experiments demonstrated that YY1 was highly expressed in OC to boost OC angiogenesis. Specifically, YY1 can stabilize hypoxia-inducible factor 1α (HIF1A) expression by competitively binding to WD repeat domain-containing 7 (FBXW7), thereby facilitating the transcriptional activation of angiogenesis genes. Finally, we demonstrated through rescue experiments that targeting the YY1/HIF1A axis can repress OC angiogenesis.</div></div><div><h3>Conclusion</h3><div>Through single-cell transcriptomics analysis combined with cell experiments, we proved the specific mechanism by which YY1 affects the angiogenesis ability of OC. YY1 affects the expression of angiogenesis genes by modulating the FBXW7/HIF1A axis.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111916"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265771","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":"2025-07-01","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":"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":"2025-07-01","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":"Implications of seven NTCP mutations for receptor stability and Hepatitis B Virus infectivity: A computational analysis","authors":"Amina Kardoudi ,&nbsp;Salaheddine Redouane ,&nbsp;Salma Madihi ,&nbsp;Thomas Jackson ,&nbsp;Abdelouaheb Benani","doi":"10.1016/j.mrfmmm.2025.111921","DOIUrl":"10.1016/j.mrfmmm.2025.111921","url":null,"abstract":"<div><div>Hepatitis B is a widespread viral infection and a major global public health concern. The human sodium taurocholate co-transporter polypeptide (NTCP) serves as a key receptor for the hepatitis B virus (HBV), enabling its entry into hepatocytes. Understanding how specific NTCP mutations influence its stability and interaction with HBV is critical for elucidating mechanisms of viral infectivity and resistance. This study evaluates the impact of seven non-synonymous NTCP mutations on receptor stability and HBV binding using a comprehensive bioinformatics approach. Mutant NTCP/HBsAg complexes were generated via HADDOCK, and binding affinities were predicted using PRODIGY. Molecular dynamics simulations with GROMACS further assessed the stability and behavior of NTCP/PreS1 complexes. Our findings reveal that V160M and S267F significantly reduce complex stability and binding affinity, suggesting a potential role in natural resistance to HBV infection. Mutations I88T and R84W moderately affect NTCP–HBV interactions, while V200M, I223T, and I279T show minimal impact, maintaining wild-type reference complex characteristics. This study highlights the differential effects of NTCP mutations on HBV infectivity, providing insights into host susceptibility and resistance. The integrative computational strategy offers a robust framework for understanding HBV-host interactions and may aid in identifying novel therapeutic targets.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111921"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608155","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}