Molecular Carcinogenesis最新文献

{"title":"PLOD2 Promotes Cutaneous Squamous Cell Carcinoma Progression in Association With STAT3-Related ERK and AKT Pathways.","authors":"Ningyi Xian, Ziwei Wang, Bingqing Wang, Xiaofei Wang, Yan Zheng","doi":"10.1002/mc.70102","DOIUrl":"10.1002/mc.70102","url":null,"abstract":"<p><p>Cutaneous squamous cell carcinoma (cSCC) is a malignant skin cancer which is derived from epidermal keratinocytes, and long-term exposure to ultraviolet rays is its main risk factor. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is a crucial gene for the formation and stability of collagen intermolecular cross-links, being vital in the development of cancer. Nevertheless, the interaction between cSCC and PLOD2 has not been elucidated. Here, we found PLOD2 upregulated in human cSCC. Its knockdown in cSCC cells suppressed proliferation, migration, invasion, and angiogenesis while inducing apoptosis and cell cycle arrest; overexpression promoted these malignant phenotypes. In mouse xenografts, PLOD2 knockdown inhibited tumor growth and collagen deposition. Furthermore, in a DMBA/TPA-induced carcinogenesis model, topical PLOD2 inhibition by minoxidil suppressed tumor development as well. Mechanistically, our studies revealed that PLOD2 acts as a key downstream effector of STAT3 to activate ERK and AKT signaling evidenced by rescue experiments. As a result, our study not only establishes the STAT3/PLOD2/ERK-AKT axis as a key driver of cSCC but also identifies the clinically approved drug minoxidil as a potent PLOD2 inhibitor, demonstrating immediate promise as a repurposed therapeutic agent.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"615-629"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326691","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":"Downregulation of ESRP2 Promotes Breast Cancer Cell Migration by Activating EMT Transcription Program Through Modulation of ENAH Variable Splicing.","authors":"Yuting Chen, Huancun Feng, Chengkuan Zhao, Linting Huang, Zirou Liao, Wang Chen, Jian Zou, Shuyao Zhang","doi":"10.1002/mc.70093","DOIUrl":"10.1002/mc.70093","url":null,"abstract":"<p><p>Epithelial splicing regulatory protein 2 (ESRP2) is a splicing regulator specific to epithelial cell types. Multiple studies have found that its expression is abnormal in various tumors, influencing their occurrence, development, or prognosis. Our previous research indicated that down-regulating ESRP2 can suppress the proliferation of breast cancer (BC) cells, specifically the MCF-7 line. To delve deeper into the role of ESRP2 in BC cells, we investigated its impact on the migration of BC cells in vitro and the underlying molecular mechanisms. The outcomes of the in vitro scratch assay and Transwell assay initially confirmed that ESRP2 hinders the migration of both MCF-7 and MDA-MB-231 cells, and that reducing ESRP2 expression enhances their migratory capacity. We demonstrated that the down-regulation of ESRP2 can boost the migration ability of MCF-7 cells, and increase the mRNA expression of epithelial-mesenchymal transition (EMT) transcription factor ZEB2 and related markers N-cadherin and Vimentin. This suggests that ESRP2 plays a potential regulatory role in inhibiting EMT transcription program. Additionally, results from RNA sequencing and agarose electrophoresis gel experiments predict that down-regulating ESRP2 may promote exon skipping of the ENAH gene by modulating the alternative splicing of genes associated with cell migration, driving the shift of MCF-7 cells from an epithelial to a mesenchymal phenotype. Our research reveals a novel mechanism by which ESRP2 affects BC metastasis through post-transcriptional regulation. ESRP2 may present as a promising biomarker in combating BC cell migration by targeting EMT.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"545-555"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150473","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":"Whole-Genome Bisulfite Sequencing Identifies Blood-Based DNA Methylation Biomarker for Hepatocellular Carcinoma.","authors":"Junsheng Zhao, Sijia Shen, Junjie Zhang, Ying Xu, Jing Peng, Hainv Gao, Lanjuan Li","doi":"10.1002/mc.70101","DOIUrl":"10.1002/mc.70101","url":null,"abstract":"<p><p>Functional DNA methylation abnormalities are a hallmark of human cancers and may be a promising biomarker for their early diagnosis. Moreover, the largest methylation differences can improve the sensitivity of noninvasive diagnoses of solid tumors. We combined whole-genome bisulfite sequencing (WGBS) and mRNA-seq data from 33 paired hepatocellular carcinoma (HCC) and adjacent tissues to identify methylation markers that could be used for noninvasive diagnosis in blood samples. Methylation markers were selected according to the following criteria: differentially methylated regions (DMR) located in the promoter region with large differences in methylation (Δβ > 0.3) and inverse correlation with matched gene expression (cor < -0.3). Cell-free DNA (cfDNA) from 48 patients with HCC and 24 normal participants was used to verify the performance of meTSPYL5 using qMSP. Integrated WGBS and transcriptomic data analysis identified eight target promoter hyper-DMRs. After confirming the WGBS profiles of genes in peripheral blood mononuclear cells, meTSPYL5 was selected to further verify the plasma cfDNA samples by qMSP. The results of plasma validation showed that the methylation detection of meTSPYL5 was sensitive for identifying HCC, with a sensitivity and specificity of 85.4% and 100%, respectively. Pan-cancer analysis found that the methylation level of TSPYL5 was elevated in multiple cancer types, indicating that it lacks cancer-type specificity; however, this result does not affect its application value in monitoring high-risk populations of HCC. By analyzing and integrating all available high-throughput epigenomic and transcriptomic data from human HCC tissues, we identified eight regions as potential diagnostic biomarkers for HCC. Integrative analyses of epigenomic and transcriptomic data provide an efficient method to identify diagnostic biomarkers for human cancers. Methylated TSPYL5 in plasma is a promising biomarker for the detection and screening of HCC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"603-614"},"PeriodicalIF":3.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13067798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326732","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":"CRISPR-Based Gene Dependency Screens Reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer.","authors":"Shawn Noronha, Yue Liu, Gaga Geneti, Haojian Li, Xiaolin Wu, David Sun, Vaibhavi Gujar, Takashi Furusawa, Alexei Lobanov, Maggie Cam, Lipika R Pal, Nishanth U Nair, Chi-Ping Day, Eytan Ruppin, Chandrayee Ghosh, Jiangnan Hu, Bhavishya Ramamoorthy, Suresh Kumar, Thorkell Andresson, King Chan, Maura O'Neill, Raj Chari, Yves Pommier, Jaydira Del Rivero, Urbain Weyemi, Electron Kebebew, Myriem Boufraqech","doi":"10.1002/mc.70122","DOIUrl":"https://doi.org/10.1002/mc.70122","url":null,"abstract":"<p><p>Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer. Despite recent advances in treating BRAFV600E-driven ATC, therapy resistance remains a significant challenge, often resulting in disease progression and death. Leveraging a focused CRISPR/KO screen in parallel with a CRISPR/activation screen, both tailored on response to BRAFV600E inhibitor treatment, we identified TAZ (encoded by WWTR1 gene) deficiency as synthetically lethal with BRAF inhibitor in ATC. TAZ is overexpressed in ATC compared to well-differentiated thyroid tumors. We demonstrate that TAZ-deficient ATC cells display heightened sensitivity to BRAF inhibitors. Using gene essentiality score across cancer cell lines, we found that BRAFV600E-driven cancers are highly sensitive to TAZ loss, unlike their counterparts with wild-type BRAF and non-BRAFV600E. Mechanistically, we demonstrate that dabrafenib triggers the Unfolded Protein Response (UPR) under ER stress and suppresses protein synthesis. TAZ loss represses the UPR, reverses the inhibition of protein synthesis, and triggers increased cell death by ferroptosis in dabrafenib-treated ATC. Collectively, our findings unveil TAZ as a new target to overcome resistance to BRAF inhibitors in undifferentiated thyroid cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776971","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":"Next-Generation Sequencing-Based Analysis of the Genetic Mutation Spectrum in Colorectal Cancer: A Large Single‑Center Study From Southeast China With Cross‑Population Comparison.","authors":"Huijuan Xu, Ruichen Luo, Weiyuan Chen, Qi Sun, Huan Chen, Kun Liu, Jun Hou","doi":"10.1002/mc.70123","DOIUrl":"https://doi.org/10.1002/mc.70123","url":null,"abstract":"<p><p>Colorectal cancer (CRC) exhibits considerable molecular heterogeneity. This study aimed to delineate the mutational landscape and investigate the associations between frequently mutated genes and key clinicopathological features in a single-center cohort of CRC patients using next-generation sequencing (NGS). This study included 381 patients with pathologically confirmed colorectal cancer. Tumor tissue samples were collected and subjected to targeted sequencing and variant analysis of 40 cancer-related genes using an NGS platform. Associations between gene mutation status and clinicopathological features-including tumor location, clinical stage, and MSI status-were assessed using the χ² test. Sequencing analysis revealed that 12 patients harbored no detectable mutations in the targeted genes. Among the remaining 369 patients, somatic variants were identified across 30 genes. Regarding mutational patterns, 115 cases (30.2%) exhibited single-gene mutations, 158 cases (41.5%) showed two co-occurring mutations, and 96 cases (25.2%) carried alterations in three or more genes. The most frequently mutated genes were TP53 (76.9%), KRAS (47.8%), and PIK3CA (18.9%). TP53 mutations were significantly enriched in left-sided colon cancers (p < 0.0001). In contrast, both KRAS (p = 0.010) and PIK3CA (p = 0.001) mutations were significantly associated with right-sided colon cancers. Furthermore, the frequency of PIK3CA mutations was significantly higher in MSI-high tumors compared to MSS tumors. This study demonstrates significant associations between specific gene mutations and distinct clinicopathological characteristics. The findings underscore the importance of integrating molecular profiling with conventional clinicopathological parameters for precise stratification.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776962","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":"Liquiritin Enhances Chemosensitivity to Doxorubicin in Breast Cancer by Promoting Ubiquitination-Mediated Degradation of MCL1.","authors":"Dunying Wang, Yunyun Sun, Tian Tang, Xiaochen Shi","doi":"10.1002/mc.70119","DOIUrl":"https://doi.org/10.1002/mc.70119","url":null,"abstract":"<p><p>Breast cancer (BC) represents a life-threatening malignant disease that profoundly endangers women's health, with chemoresistance restricting treatment efficacy. Liquiritin (LIQ) has shown great potential in cancer therapy, yet its effect on the chemosensitivity of BC cells remains unclear. BC cells were treated with different concentration gradients of Doxorubicin (DOX) and LIQ. Cell counting kit-8 (CCK-8) assay, colony formation assay, and flow cytometry were employed to determine cell proliferation, apoptosis, and cell cycle progression. Western blot was applied to examine the levels of apoptosis-related proteins. The cycloheximide chase assay and immunoprecipitation were conducted to examine the degradation and ubiquitination levels of Myeloid Cell Leukemia-1 (MCL1). Finally, a BC xenograft mouse model was constructed to confirm the role of LIQ in vivo. In vitro experiments demonstrated that LIQ enhanced the chemosensitivity of BC cells to DOX and synergistically promoted DOX-induced apoptosis and cell cycle arrest. Moreover, the interaction between LIQ and DOX promoted the ubiquitination-mediated degradation of MCL1. Overexpression of MCL1 eliminated the sensitizing effect of LIQ to DOX. Additionally, LIQ enhanced the chemosensitivity of DOX in BC xenograft mice. LIQ enhanced DOX chemosensitivity in BC cells and xenograft models by promoting ubiquitination-mediated degradation of MCL1.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717380","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":"Deciphering MFAP5+ Fibroblasts in Pancreatic Cancer Progression via Multi-Regional Single-Cell RNA Sequencing With Experimental Validation.","authors":"Wei Wei, Wuyang Zhang, Min Wang, Yuyi Liu, Shuai Ming, Mengru Li, Peng Cheng, Wei Cao, Jingyu Li, Dan Shi, Bin Wang","doi":"10.1002/mc.70114","DOIUrl":"https://doi.org/10.1002/mc.70114","url":null,"abstract":"<p><p>Recent studies highlight the critical role of cancer-associated fibroblasts (CAFs) in tumor invasion, but research on the regulation of MFAP5+ fibroblasts by the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) remains limited. Therefore, understanding the function, spatial distribution, and communication dynamics of MFAP5+ fibroblasts within the PDAC tumor microenvironment is essential. We used multi-regional single-cell RNA sequencing to examine the biological characteristics of MFAP5+ fibroblasts in PDAC. A pseudo-time analysis technique was then applied to infer the evolution of CAF subtypes. To investigate this functional role and spatial relationship, we employed multiplex immunofluorescence to observe the spatial distribution of MFAP5+ fibroblasts and endothelial cells. Our study investigated PDAC tumor heterogeneity through a comprehensive analysis of 59,829 cells, which integrated our own multi-regional sampling (GSE285264) with publicly available datasets (GSE277782, GSE155698, GSE212966). We found that MFAP5+ fibroblasts were associated with FABP4+ endothelial cells and VWF+ endothelial cells via key tumor-promoting pathways (e.g., TGF-β, VEGF, FGF). Multiplex immunofluorescence and semi-quantitative analysis confirmed increased prevalence of FABP4+ and VWF+ endothelial cells in areas with high MFAP5+ fibroblast expression, along with elevated VEGF and FGF signaling. Our study reveals a potential pro-tumorigenic mechanism of MFAP5+ fibroblasts in PDAC, suggesting that the MFAP5+ fibroblast-endothelial cell axis may represent a potential target for future therapeutic strategies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717373","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":"RUNX1 Directly Activates WNT2 to Orchestrate Tumor-Associated Macrophage Reprogramming in Colorectal Cancer.","authors":"Wei Sun, Xiaohui Ren, Shuqing Wei, Lingzhi Cui, Jingjing Li, Xiaolu Ren, Yong Zhang","doi":"10.1002/mc.70116","DOIUrl":"https://doi.org/10.1002/mc.70116","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs), particularly the M2 subtype, foster immune suppression and metastasis in colorectal cancer (CRC). Although WNT2 is upregulated in several cancers and RUNX1 is an oncogenic transcription factor in solid tumors, whether a RUNX1-WNT2 axis orchestrates M2 polarization and CRC progression has been unclear. We profiled RUNX1 and WNT2 expressions and correlations with M2 markers in TCGA_COAD/READ using GEPIA and validated findings in 36 paired CRC and adjacent tissues by qRT-PCR, Western blotting, and immunohistochemistry. Functional effects of WNT2 were tested in CRC cell lines (SW480, SW620) using CCK-8, colony formation, and Transwell assays after shRNA knockdown. A Transwell co-culture with PMA-differentiated THP-1 macrophages assessed polarization by flow cytometry (CD86, CD206) and Western blotting (CD68, MAC2, CD20), alongside ELISAs for CCL2, CSF1, and IL-10. RUNX1 regulation of WNT2 was examined by JASPAR/UCSC prediction, ChIP-qPCR, and dual-luciferase reporter assays. In vivo, we evaluated tumor growth (subcutaneous xenografts) and lung metastasis (tail-vein injection) following WNT2 knockdown and performed rescue studies using an IL-10 neutralizing antibody or the CSF1R inhibitor BLZ945. WNT2 was significantly overexpressed in CRC versus normal tissues and positively associated with M2-TAM signatures. WNT2 knockdown curtailed CRC cell viability, clonogenicity, migration, and invasion, reduced secretion of CCL2/CSF1/IL-10 and shifted THP-1 macrophages from an M2-like (CD206⁺) toward an M1-like (CD86⁺) phenotype. RUNX1 expression correlated with WNT2; RUNX1 loss decreased WNT2, while overexpression increased it. ChIP and reporter assays demonstrated direct RUNX1 binding and transcriptional activation of the WNT2 promoter. In vivo, WNT2 silencing reduced tumor volume and weight, increased CD86⁺ and decreased CD206⁺ macrophages in tumors, and diminished lung metastatic burden. Furthermore, blocking M2 polarization (anti-IL-10) or depleting macrophages (BLZ945) mitigated WNT2-driven tumor growth and M2 infiltration. RUNX1 directly activates WNT2 to promote cytokine production and M2 macrophage polarization, thereby accelerating CRC growth and metastasis. These findings suggest that targeting the RUNX1-WNT2 axis and its downstream macrophage programs may offer a therapeutic strategy and potential biomarker framework for CRC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691047","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":"The Role of CD44, CALCOCO2, ALDH4A1, and CLEC16A in the Cross-Talk Model of Epilepsy and Thyroid Cancer Progression.","authors":"Si Ying Wang, Tianyu Liu, Dechun Zhang, Weixuan Liu, Meng Qian, Rongfang Li, Zhen Yu Liu, Pei Wu","doi":"10.1002/mc.70118","DOIUrl":"https://doi.org/10.1002/mc.70118","url":null,"abstract":"<p><p>Epilepsy and thyroid cancer are prevalent disorders with distinct etiologies; however, emerging evidence suggests the presence of shared molecular mechanisms that remain largely unexplored. In this study, we aimed to identify and characterize common hub genes and potential diagnostic markers linking these two conditions using comprehensive in silico and in vitro approaches. Differentially expressed genes (DEGs) were analyzed from epilepsy datasets (GSE44456, GSE186334) and thyroid cancer datasets (GSE60542, GSE153659), leading to the identification of four shared hub genes: CD44, CALCOCO2, ALDH4A1, and CLEC16A. Expression validation using RT-qPCR confirmed consistent patterns, with CD44 and CLEC16A significantly upregulated and CALCOCO2 and ALDH4A1 downregulated in disease cell lines compared to controls. Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic potential for these genes in both diseases, with area under the curve (AUC) values exceeding 0.90. Functional enrichment and pathway analyses revealed that these genes are involved in oncogenic signaling, immune regulation, and tumor progression. Genetic alteration analysis indicated frequent mutations and copy number variations, while promoter methylation profiling suggested epigenetic regulation associated with disease outcomes. Survival analysis further identified ALDH4A1 and CLEC16A as prognostic markers. Moreover, in vitro and in vivo experiments demonstrated that CD44 and CLEC16A regulate cellular proliferation, migration, and clonogenicity through extracellular matrix (ECM)-receptor interactions involving CCL5, STAT3, CXCR4, and RAC1 signaling pathways. Collectively, these findings provide new insights into the shared molecular landscape of epilepsy and thyroid cancer, highlighting potential diagnostic biomarkers and therapeutic targets.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639421","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":"USP15 Promotes Pancreatic Cancer Progression and Cisplatin Resistance By Activating DNA Damage Repair.","authors":"Zhigang Ma, Hengzhen Li, Guangchun Zeng, Guangtao Jiao, Shuling Han, Yuli Ruan, Ya Lan, Xin Guan, Yushuai Song, Chao Liu, Xiaolin Lu, Zhiwei Li","doi":"10.1002/mc.70105","DOIUrl":"https://doi.org/10.1002/mc.70105","url":null,"abstract":"<p><p>Cisplatin (DDP) is a key chemotherapeutic agent for pancreatic cancer (PC), but its efficacy is often limited by the development of DNA damage repair (DDR)-mediated resistance. Ubiquitin-specific peptidase 15 (USP15) is known to activate DDR pathways; however, its specific role and clinical relevance in PC remain poorly understood. We analyzed USP15 expression and its clinical significance using public databases, tissue microarrays, and cell lines through RT-qPCR, Western blot, and immunohistochemistry. The effect of USP15 on DDP resistance was evaluated using colony formation and flow cytometry assays. Protein interaction between USP15 and POLE3 was confirmed by Co-IP. DNA damage levels were assessed via immunofluorescence staining, neutral comet assays, and host cell reactivation. Both loss-of-function and gain-of-function studies of USP15 were conducted in a mouse xenograft model. We found that USP15 was significantly upregulated in PC tissues and correlated with poor patient prognosis. Overexpression of USP15 enhanced DDP resistance in PC cells in vitro and in vivo. Enrichment analysis indicated a strong association between USP15 expression and DDR-related genes. Mechanistically, USP15 was found to bind to POLE3 and suppress its ubiquitination-dependent degradation, thereby facilitating DDP-induced DNA damage repair. Our findings highlight the upregulation and prognostic value of USP15 in PC, and uncover its role in promoting DDR-mediated DDP resistance through stabilization of POLE3.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639435","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}