Carcinogenesis最新文献

{"title":"Core transcriptional regulatory circuit-regulated IGF2BP3 stabilizes E2F2 mRNA via m6A modification in neuroblastoma.","authors":"Pengcheng Yang, Jianwei Wang, Ziheng Wu, Ran Zhuo, Yanling Chen, Gen Li, Yanfang Tao, Xiaolu Li, Fang Fang, Di Wu, Yang Yang, Hongli Yin, Guanghui Qian, Hairong Wang, Xin Li, Juanjuan Yu, Randong Yang, Yunyun Xu, Zhiheng Li, Lei Shi, Zimu Zhang, Jian Pan, Jian Wang","doi":"10.1093/carcin/bgaf040","DOIUrl":"10.1093/carcin/bgaf040","url":null,"abstract":"<p><p>Neuroblastoma (NB) is a pediatric tumor with diverse outcomes and unknown underlying mechanisms. The core transcriptional regulatory circuit (CRC) and N6-methyladenosine (m6A) are key factors that control cell identity and fate. IGF2BP3 is an m6A reader protein that is transcriptionally regulated by CRC transcription factors (TFs). In NB, this molecule is abundantly expressed, and there is a clear correlation between its expression and a bad prognosis. We mechanistically demonstrated that IGF2BP3 promotes E2F2 mRNA expression through m6A, which is correlated with high risk and poor prognosis in NB patients. We showed that the CRC TF-IGF2BP3-E2F2 regulatory axis forms an oncogenic network that drives NB development and progression. Overall, we investigated the molecular mechanism by which IGF2BP3, a m6A-reading protein that is regulated by CRC TFs, regulates E2F2 mRNA expression in an m6A-dependent manner. This study highlights the therapeutic potential of disrupting this axis with m6A-targeted interventions.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of prediagnostic serum liver enzyme levels with lung cancer risk in predominantly low-income African and European Americans.","authors":"Shuai Xu, Hui Cai, Jie Wu, Jiajun Shi, Regina Courtney, Hyung-Suk Yoon, Xiao-Ou Shu, William J Blot, Wei Zheng, Qiuyin Cai","doi":"10.1093/carcin/bgaf052","DOIUrl":"10.1093/carcin/bgaf052","url":null,"abstract":"<p><p>Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646 matched controls with baseline serum alanine aminotransferase (ALT) and of 548 cases and 1032 matched controls with baseline serum alkaline phosphatase (ALP) nested within the Southern Community Cohort Study. Conditional logistic regression and generalized linear models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among all study participants and by stratification of potential effect modifiers. Most participants had clinically normal liver enzyme levels. Higher serum ALT levels were associated with reduced LC risk. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (Ptrend < .01), respectively. The inverse association was observed in African Americans (AAs) and European Americans, which was especially prominent among men, and was seen in both those diagnosed within [ORT3 versus T1 = 0.41 (0.19-0.88)] and beyond [ORT3 versus T1 = 0.35 (0.17-0.73)] a median follow-up time of 39 months. Higher serum ALP levels were associated with increased LC risk among AA men only [ORT3 versus T1 = 2.01 (1.19-3.39)] (Ptrend < .01). Our results indicate that in a predominantly low-income American population, higher serum ALT levels may be related to lower LC risk. Further studies are warranted to confirm our findings and elucidate the potential underlying biological mechanisms of the associations.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis.","authors":"","doi":"10.1093/carcin/bgaf042","DOIUrl":"10.1093/carcin/bgaf042","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"46 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HECTD3 E3 ligase mediates ubiquitination of AKT-phosphorylated CMTM3 in HER2-overexpressed breast cancer cells.","authors":"Jun Wang, Delong Wang, Xinxing Zhang, Xiaoyang Xu","doi":"10.1093/carcin/bgaf048","DOIUrl":"10.1093/carcin/bgaf048","url":null,"abstract":"<p><p>CKLF-like MARVEL transmembrane domain-containing (CMTM) proteins play pivotal roles in tumorigenesis and cancer progression across various malignancies. However, their expression profiles and regulatory mechanisms in distinct subtypes of breast cancer remain largely undefined. In this study, we systematically analysed the expression of all nine CMTM family members across major molecular subtypes of breast cancer, including Luminal A, Luminal B, HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Among these, CMTM3 was uniquely downregulated in Luminal B and HER2+ breast cancer cells and functioned as a tumor suppressor. Overexpression of HER2 in normal breast epithelial cell lines led to the phosphorylation of CMTM3. Molecular and biochemical analyses revealed that HER2 overexpression activated the downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (also known as RAC-Alpha Serine/Threonine-Protein Kinase, AKT) signaling pathway in Luminal B and HER2+ breast cancer cells. AKT1 directly phosphorylated CMTM3 at serine 181 (Ser181), a modification that facilitated its recognition and ubiquitination by the E3 ligase HECT domain E3 ubiquitin protein ligase 3 (HECTD3), ultimately targeting CMTM3 for proteasomal degradation. Functional assays demonstrated that either knockdown of HECTD3 or pharmacological inhibition of PI3K/AKT signaling stabilized CMTM3 protein levels. Moreover, reintroducing a nonphosphorylatable CMTM3 mutant (CMTM3S181A) into CMTM3 knockout breast cancer cells resulted in significantly reduced proliferation, colony formation, invasive capacity, and in vivo tumor growth compared with cells expressing wild-type CMTM3 (CMTM3WT). Collectively, these findings reveal a previously unrecognized posttranslational regulatory mechanism of CMTM3 and suggest that targeting the PI3K/AKT-HECTD3-CMTM3 axis may offer a promising therapeutic approach for treating HER2+ breast cancers.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Δ133p53 isoform enhances TLR4 function to promote tumour growth.","authors":"Sasini Polwatta Lekamlage, Alexandra N Boix De Jesus, Adriana Machado Saraiva, Catherine Drummond, Harrison Dolan, Francesc March de Ribot, Janice A Royds, Sunali Mehta, Antony W Braithwaite, Noelyn A Hung, Tania L Slatter","doi":"10.1093/carcin/bgaf051","DOIUrl":"https://doi.org/10.1093/carcin/bgaf051","url":null,"abstract":"<p><p>Tumour protein 53 (TP53) acts as a tumour suppressor and is often mutated in cancer. Isoforms of TP53, such as the Δ133p53 family, can promote tumour growth and metastasis. Therefore, targeting Δ133p53 function may represent a new strategy for preventing tumour metastasis. To inform the identification of proteins to target in Δ133p53-expressing tumours, changes at the cell surface were characterised. Inhibition of cell surface trafficking in a mouse model syngrafted with tumours expressing proteins similar to Δ133p53 (Δ122p53) was associated with reduced tumour growth and metastasis. After confirming that changes at the cell surface were important for Δ133p53 tumour promotion, characterisation of protein changes at the Δ133p53/Δ122p53 cell surface revealed increased expression of the toll-like receptor 4 (TLR4) and the TLR4 agonist, apoptosis inhibitor 5. Furthermore, inhibition of TLR4 was sufficient to reduce Δ122p53 tumour growth. Altogether, these results suggest a role for Δ133p53 in contributing to tumour progression by stimulating TLR4 function. Furthermore, targeting changes at the cell surface can reduce Δ133p53 tumour promotion.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRINP3 promotes lung adenocarcinoma by enhancing CLOCK-mediated transcriptional regulation of CRYZL1 and activating the AKT pathway.","authors":"Ye Zhang, Cheng Huang, Yeye Chen, Lei Liu, Shanqing Li","doi":"10.1093/carcin/bgaf039","DOIUrl":"https://doi.org/10.1093/carcin/bgaf039","url":null,"abstract":"<p><p>Lung cancer, particularly lung adenocarcinoma (LUAD), is the leading cause of cancer-related death globally. This study investigated the role of BRINP3 in LUAD. Immunohistochemical analysis revealed significantly upregulated BRINP3 expression in LUAD tissues compared to normal tissues, mainly located in the cytoplasm and positively correlated with tumor progression. RNA sequencing data from the TCGA-LUAD database corroborated these findings. Elevated BRINP3 expression was associated with advanced tumor stages, higher malignancy grades, and increased risk of lymphatic metastasis. Functional studies showed that BRINP3 knockdown inhibited cell proliferation, colony formation, and migration, while promoting apoptosis. Conversely, BRINP3 overexpression enhanced these malignant behaviors. Gene expression profiling identified CLOCK and CRYZL1 as potential BRINP3 targets, with BRINP3 interacting with CLOCK to regulate CRYZL1 transcription. Additionally, BRINP3 activated the AKT signaling pathway to promote LUAD progression. In vivo experiments validated the tumor-suppressing effects of BRINP3 knockdown, reducing tumor growth and metastatic potential. In conclusion, BRINP3 played a crucial role in LUAD development and progression by regulating CLOCK-mediated transcriptional regulation of CRYZL1 and activating the AKT signaling pathway. BRINP3 knockdown inhibited LUAD cell malignancy and might represent a potential therapeutic target.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive Epidermal Expression of Osteopontin in Osteopontin-Null Mice Restores Ultraviolet B-Induced Cutaneous Squamous Cell Carcinomas to Wild-Type Levels.","authors":"Chu-Fang Chou, Yun Huang, Jeremy B Foote, Yu-Hua Hsieh, Hui-Chien Kuo, David K Crossman, Michael R Crowley, Zorica Janjetovic, Andrej T Slominski, Craig Elmets, Pi-Ling Chang","doi":"10.1093/carcin/bgaf034","DOIUrl":"10.1093/carcin/bgaf034","url":null,"abstract":"<p><p>Studies of osteopontin (OPN)-null mice have supported the role of OPN as a critical factor in the promotion of skin tumorigenesis. OPN is a highly inducible integrin- and CD44-interacting acidic glycoprotein with pleiotropic functions. In various cancers, elevated levels of OPN from cancer and inflammatory cells are secreted into the microenvironment and the bloodstream. To determine whether OPN expressed by keratinocytes without contribution from activated resident and infiltrating inflammatory cells promotes cutaneous tumorigenesis, transgenic mice with constitutive epidermal expression of OPN in an OPN-null background (tg(K14-OPN)) were generated. In photocarcinogenesis studies, tumor multiplicity and the incidence of cutaneous squamous cell carcinoma (cSCC) were similar in the tg(K14-OPN) and wild-type (WT) mice. The incidence of cSCC was significantly higher in the WT than in OPN-null mice. This incidence did not reach significance in tg(K14-OPN) and OPN-null mice, likely due to fewer mice. Tg(K14-OPN) mice exhibited reduced keratinocyte apoptosis but not enhanced epidermal hyperplasia after ultraviolet B (UVB) exposure compared to OPN-null mice. Additionally, tg(K14-OPN) and OPN-null mice irradiated with long-term low dose UVB had significantly lower numbers of mutated p53 keratinocytes than WT mice. RNA-sequencing data from the epidermis of acute UVB-irradiated tg(K14-OPN) versus OPN-null mice compared to UVB-irradiated WT versus OPN-null mice suggests the importance of inflammation, Wnt, integrin and gonadotropin-releasing hormone receptor signaling in cutaneous tumorigenesis and implicates UVB irradiation and its induction of OPN in driving those pathways. In summary, the constitutive epidermal expression of OPN in OPN-null mice facilitates the development of cSCC comparable to WT mice.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary metabolites in association with kidney cancer risk.","authors":"Thuraya Al-Sayegh, Shuang Song, Loren Lipworth, Hui Cai, Qing Lan, Yutang Gao, Nathaniel Rothman, Qiuyin Cai, Wei Zheng, Xiao-Ou Shu","doi":"10.1093/carcin/bgaf029","DOIUrl":"10.1093/carcin/bgaf029","url":null,"abstract":"<p><p>Kidney cancer incidence has increased worldwide in recent decades. While metabolomic studies have shown promise in unveiling mechanisms underlying disease development, few studies have investigated prediagnostic urinary metabolites and kidney cancer risk. We conducted a case-control study nested within the Shanghai Women's and Men's Health Studies to prospectively investigate the association between urinary metabolites and kidney cancer risk to understand its etiology and the underlying biological mechanisms. Two hundred primary kidney cancer cases and their individually matched controls were included. A total of 1301 metabolites were evaluated, and 67 metabolites were found nominally associated with kidney cancer using conditional logistic regression. After backward selection, 11 urine metabolites remained significantly associated with kidney cancer: lipids (e.g. picolinoylglycine, odds ratio [OR]; 95% confidence interval [CI]: 2.01 [1.44, 2.79], and pregnanediol-3-glucuronide, OR; 95% CI: 0.56 [0.39, 0.82]), xenobiotics (e.g. beta-guanidinopropanoate, OR; 95% CI: 1.75 [1.32, 2.32] and 4-vinylphenol sulfate, OR; 95% CI: 0.66 [0.49, 0.90]), and nucleotides (e.g. allantoic acid, OR; 95% CI: 0.71 [0.54, 0.92]). Time lag analysis showed that metabolite-kidney cancer associations were stronger for beta-guanidinopropanoate (OR; 95% CI: 8.22 [1.68, 40.18]) and picolinoylglycine (OR; 95% CI: 6.45 [1.28, 32.43]), but weaker for allantoic acid (OR; 95% CI: 0.87 [0.37, 2.06]) and 3-methylglutarate/2-methylglutarate (OR; 95% CI: 0.62 [0.19, 2.00]) when urinary samples were collected within 3 years between urine sample collection and cancer diagnosis (Pinteraction < .05 for all). Future metabolomics studies with large sample sizes, particularly from multiple ancestry populations, are needed to validate our findings.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study of early-stage non-small cell lung cancer prognosis: a pooled analysis in the International Lung Cancer Consortium.","authors":"Mei Dong, Abhinav Thakral, Karl Smith- Byrne, Yohan Bosse, Hufeng Zhou, Yi Zhang, Joshua Atkins, Philip Haycock, M Catherine Brown, Kiera Murison, Wim Timens, Don D Sin, Jui Kothari, Aurélie A G Gabriel, David Zaridze, Milan Savic, Jolanta Lissowska, Beata Świątkowska, Vladimir Janout, Ivana Holcatova, Anush Mukeria, Guillermo Fernandez-Tardon, Michael P A Davies, Matthew Triplette, Matthew B Schabath, Angeline S Andrew, Chu Chen, Fiona Taylor, John K Field, Adonina Tardon, Sanjay S Shete, Paul Brennan, Maria Teresa Landi, James McKay, Christopher I Amos, Xihong Lin, David C Christiani, Rayjean J Hung, Geoffrey Liu, Wei Xu","doi":"10.1093/carcin/bgaf031","DOIUrl":"10.1093/carcin/bgaf031","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale genome-wide association prognostic study using data from the International Lung Cancer Consortium (ILCCO) through a two-phase analysis. Phase 1 includes the discovery of genome-wide association studies analysis using a multivariable Cox PH model on 3428 NSCLC patients of European ancestry from 10 ILCCO participating studies to identify genetic variants associated with overall survival and validation analysis for genome-wide significant variants (P-value ≤5 × 10-8) using the Cancer Genome Atlas (TCGA). Phase 2 aims to identify causal variants using functional analyses of genome-wide significant and suggestive variants (P-value ≤1 × 10-5), including variant-epigenetic functional annotation (FAVOR), CHIP-seq data, variant-gene expression association, and colocalization analysis. We identified two significant variants; of those, a locus at 9q21.31 (rs117979484) was significant at the genome-wide level (P = 3.67 × 10-8) and validated in TCGA (P = 0.03). Three suggestive variants were found to have a putative epigenetic function: intronic variants rs149281784 (BCL7B gene) and rs148031766 (POM121 gene) both located at 7q11.23 and in moderate linkage disequilibrium with each other; and variant rs2471630 (SRCIN1 gene; 17q12). Specifically, variants rs149281784 and rs148031766 have potential regulatory roles in the transcriptional activation of the BCL7B gene and POM121 gene. Exploratory survival analyses in the squamous cell carcinomas subgroup also identified a significant variant, rs138467404 (GRHL-2 gene; 8q22.3) at a genome-wide level (P = 4.75 × 10-8) and validated by TCGA (P = 0.02). These new findings indicate potential novel pathways associated with early-stage NSCLC prognosis. Future research may validate additional genome-wide suggestive variants as being relevant for lung cancer outcomes.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoresistance and immune evasion in hepatocellular carcinoma: the role of miRNA-425-5p.","authors":"Xinghe Pan, Junliang Liu, Yitong Zhang, Chenglin Sun, You Li","doi":"10.1093/carcin/bgaf012","DOIUrl":"10.1093/carcin/bgaf012","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) represents a significant global health challenge, with chemoresistance severely limiting treatment efficacy. This study investigates the role of miRNA-425-5p in exosomes in modulating the tumor microenvironment (TME) and contributing to chemoresistance and immune evasion in HCC. Differentially expressed miRNAs were identified using TaqMan low-density array technology in serum samples from XELOX-resistant and -sensitive HCC patients. miRNA-425-5p expression was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Exosomes from HCC cell lines were characterized by transmission electron microscopy and nanoparticle tracking analysis. Functional assays, including luciferase reporter assays and flow cytometry, elucidated the mechanisms of miRNA-425-5p. In vivo studies with mouse xenograft models evaluated the impact of miRNA-425-5p on tumor growth and chemosensitivity. miRNA-425-5p was significantly upregulated in the serum of XELOX-resistant HCC patients and correlated with poorer survival outcomes. Exosomes from chemoresistant HCC cells exhibited increased levels of miRNA-425-5p, which, when internalized by CD4+ T cells, promoted regulatory T cell (Treg) expansion by targeting phosphatase and tensin homolog (PTEN). In vivo, miRNA-425-5p overexpression enhanced tumor growth and chemoresistance, while its inhibition reduced tumor size and increased chemosensitivity. These findings indicate that miRNA-425-5p in exosomes plays a crucial role in HCC chemoresistance and immune evasion by modulating the TME and promoting Treg expansion through PTEN targeting. miRNA-425-5p serves as a potential biomarker for predicting chemoresistance and a therapeutic target for overcoming drug resistance in HCC.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}