{"title":"A-to-I RNA Edited miR-3167 Restrains Malignant Behaviors of Lung Adenocarcinoma by Influencing SSR2-Meditated Hippo Signaling.","authors":"Dawei Qian, Dongsheng Zha, Yuanyao Sang, Jiangquan Tao, Bufeng Zhuang, Youshuang Cheng","doi":"10.1002/mc.70011","DOIUrl":"10.1002/mc.70011","url":null,"abstract":"<p><p>Recently, RNA editing, as a natural modification process of RNA molecules, has aroused extensive interest in the scientific community. This study elaborated the role and process of A-to-I RNA edited miR-3167 in lung adenocarcinoma (LUAD). RT-qPCR and Western blot analysis were employed for the detection of miRNA and gene expressions. The function of miRNA was investigated through Transwell, CCK-8 and flow cytometry assays. Dual-luciferase reporter assay was conducted to assess the link between gene and miRNA. The level of A-to-I RNA editing for miR-3167 was declined in LUAD tissues, which was linked to adverse clinical outcomes and prognosis in LUAD patients. In LUAD, ADAR2 enzyme is responsible for mediating the A-to-I RNA editing of miR-3167. Functionally, LUAD cell viability and metastasis were scarcely influenced by wt-miR-3167, while miR-3167 displayed antitumor activity in LUAD post A-to-I RNA editing. Mechanically, SSR2 is directly targeted by ed-miR-3167 in LUAD, but not wt-miR-3167. SSR2 served as a tumor promoter in LUAD progression by inactivating Hippo signaling and hindering immune infiltration. Ed-miR-3167 exerted tumor inhibitory effect in LUAD by weakening the carcinogenesis of SSR2. A-to-I RNA edited miR-3167 curbs malignant behaviors of LUAD by activating Hippo signaling through downregulating SSR2, indicating that edited miR-3167 has the potential as a therapeutic target for LUAD.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1552-1563"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591828","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":"Osteoglycin Inhibits the Progression of Lung Adenocarcinoma by Modulating ICAM1-Mediated Cell Adhesion via the PI3K/AKT Pathway.","authors":"Shangwei Xu, Chunji Chen, Hongwei Liu, Shuai Jiang, Zheng Li, Yun Wu","doi":"10.1002/mc.70007","DOIUrl":"10.1002/mc.70007","url":null,"abstract":"<p><p>Lung cancer is characterized by high aggressiveness and lethality, processing in-depth molecular mechanism investigation is particularly necessary. In our study, we found that osteoglycin (OGN) deficiency is strongly associated with a poor prognosis in lung adenocarcinoma (LUAD). OGN overexpression could inhibit the proliferation, migration, and invasion of LUAD cells. Through transcriptome sequencing analysis and experimental validation, we revealed that such OGN-mediated tumor suppression effect was related to cell adhesion function induced by ICAM1 downregulation, along with regulation by the PI3K/AKT signaling pathway. The present study demonstrated the specific mechanism of OGN involvement in LUAD progression, providing new evidence and potential targets for research on cancer suppression in LUAD.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1564-1579"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626750","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":"Mitochondrial Energy Metabolic Reprogramming Facilitates the Malignant Progression of Intrahepatic Cholangiocarcinoma.","authors":"Jun-Long Wang, Yu-Chen Pei, Qi-Zhi Liang, Xi Yu, Jia-Yi Cai, Nian-Dong Yi, Wei-Gen Wu, Yu-Ze Wang, Qi Liu, Wei Chen","doi":"10.1002/mc.23930","DOIUrl":"10.1002/mc.23930","url":null,"abstract":"<p><p>Mitochondrial function plays a crucial role in cancer development, with mitochondrial energy metabolism-related genes (MEMRGs) contributing to carcinogenesis. This study investigates the role of MEMRGs in intrahepatic cholangiocarcinoma (ICC) by analyzing RNA-seq data from TCGA and GEO databases to identify differentially expressed MEMRGs. Functional enrichment and KEGG pathway analyses revealed their significant involvement in metabolic pathways. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, two distinct ICC subtypes were identified. Tumor mutational burden (TMB), immune cell infiltration, and immune escape potential were assessed, highlighting the importance of the Hippo/YAP pathway. Cox regression analyses pinpointed key prognostic genes, including ADH1A, ADH1B, and CYP4A11. A MEMRG-based nomogram was developed that accurately predicted 1- and 3-year survival outcomes. Experimental validation showed that ADH1B suppresses ICC malignancy through the Hippo/YAP pathway. These findings suggest that MEMRGs are vital in ICC progression and immune regulation, serving as promising prognostic biomarkers and therapeutic targets, though further validation is required.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1429-1449"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369089","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}
Chelsea A Friedman, Achinto Saha, Rachel Clark, Carly Wilder, Jordan Wright, John DiGiovanni
{"title":"Synergistic Inhibition of Prostate Cancer Progression in Mice With a Combination of Curcumin and Ursolic Acid in the Diet.","authors":"Chelsea A Friedman, Achinto Saha, Rachel Clark, Carly Wilder, Jordan Wright, John DiGiovanni","doi":"10.1002/mc.70000","DOIUrl":"10.1002/mc.70000","url":null,"abstract":"<p><p>Prostate cancer (PCa) is the second leading cause of cancer-related death among American men, and its long latency offers a window for chemopreventive strategies. Phytochemicals, with their diverse impacts on cancer cell growth and metabolism, represent promising candidates for such strategies. Combining compounds like curcumin (Curc) and ursolic acid (UA), which target multiple pathways, can be advantageous in slowing tumor progression. Previous studies revealed the synergistic effects of Curc + UA in reducing tumor growth in a PCa allograft model. In this study, diet-based interventions were evaluated using two transgenic mouse models of PCa. Mice fed a Curc + UA-enriched diet exhibited significant inhibition of prostate tumor progression compared to single-agent diets in both HiMyc and PTEN knockout mouse models. Protein analyses of ventral prostate tissues from HiMyc mice indicated that the combination suppressed oncogenic signaling pathways, including STAT3, AKT, and mTORC1, while modulating cell regulatory proteins to inhibit tumor cell proliferation. Furthert mechanistic studies in mouse and human PCa cell lines confirmed that Curc + UA exerted pleiotropic effects by influencing oncogenic signaling, cell cycle regulation, mitochondrial function, unfolded protein response (UPR), and apoptosis, collectively contributing to its synergistic efficacy. These findings highlight the potential of Curc + UA to inhibit PCa progression through multitargeted mechanisms. The combination's superior efficacy over single agents underscores its promise as a chemopreventive or therapeutic strategy. This study provides a strong rationale for further mechanistic investigations and clinical development of Curc + UA for PCa prevention and treatment.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1487-1499"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575831","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}
Xinliang Gu, Danping Zhu, Youyue Li, Xinwei Liu, Xincheng Yang, Junjie Nie, Tao Xu, Huiling Sun, Bin Zhu, Yuqin Pan, Shukui Wang
{"title":"Identification of Plasma rRNA-Derived Small RNA Biomarkers for Diagnosis of Colorectal Cancer.","authors":"Xinliang Gu, Danping Zhu, Youyue Li, Xinwei Liu, Xincheng Yang, Junjie Nie, Tao Xu, Huiling Sun, Bin Zhu, Yuqin Pan, Shukui Wang","doi":"10.1002/mc.70012","DOIUrl":"10.1002/mc.70012","url":null,"abstract":"<p><p>Colorectal cancer (CRC) ranks among the most aggressive malignancies globally, with advanced-stage patients exhibiting notably low survival rates. Consequently, there is an urgent imperative to identify novel biomarkers characterized by high sensitivity and specificity. Ribosomal RNA-derived small RNAs (rsRNAs), which originate from ribosomal RNAs, represent the most prevalent small noncoding RNAs (sncRNAs) in CRC tissues and plasma. Thus, the development of a diagnostic panel comprising multiple rsRNAs holds considerable significance for CRC diagnosis. Utilizing PANDORA-seq, we have, for the first time, delineated a novel sncRNA expression profile in CRC tissues and plasma, identifying rsRNAs as the predominant sncRNAs within these contexts. We identified six rsRNAs that were significantly upregulated in CRC plasma and subsequently constructed a co-diagnostic panel. This panel demonstrated an area under the curve (AUC) value of 0.898, which increased to 0.942 when combined with clinically utilized tumor markers, indicating robust diagnostic efficacy. Our study is the first to establish that rsRNAs are the most abundantly expressed sncRNAs in CRC tissues and plasma. We have developed an rsRNA panel with substantial diagnostic efficacy in CRC plasma, presenting promising potential as diagnostic biomarkers.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1580-1590"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626749","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":"Determine the Antimetastasis Effect of Artesunate in Lung Cancer-Driven Brain Metastasis Model.","authors":"Minling Lu, Ting Wan, Qianling Huang, Jingjing Yao, Yaqiu Zheng, Shaofang Yu, Xiaomin Zhu, Xiaoyi Zeng, Zhongqiu Liu, Yuan Zheng, Linlin Lu","doi":"10.1002/mc.70010","DOIUrl":"10.1002/mc.70010","url":null,"abstract":"<p><p>Brain metastasis (BM), most vital and common metastasis phenotype occurs during tumorigenesis, the incidence of which varied remarkedly in various cancers. Overwhelming evidence suggested blood-brain barrier (BBB) can attenuate the anti-BM efficacy of chemotherapies via hindering their penetration. This study aimed to investigate the preferential cancer type that is more prone to BM, and bioactive compound that suppress BM through penetrating BBB. By intracardiac injection of lung cancer cells, breast cancer cells and melanoma cells, BM models were established. By two cycles of primary-isolation and incubation of H446-luc cells to improve the incidence of BM. Artemisinin (ART) and its derivatives were evaluated to suppress BM in vitro and in vivo. Compared to lung cancer-driven BM (66.67%), the incidence of BM in breast cancer (16.67%-33.33%) and melanoma (33.33%) were extremely low. The incidence of BM in lung cancer increased from 66.67 (1st generation) to 80% (2nd generation). Compared to other ingredients, artesunate (ARTS) exerted a more significant inhibitory effect on cell proliferation, especially in lung cancer cells. Simultaneously, ARTS suppressed lung cancer migration via decreasing N-cadherin and Snail, and enhancing E-cadherin. Most importantly, we found that ARTS could strikingly suppress tumor growth in brain with high concentration, implying that ARTS might penetrate BBB and accumulate in brain tissue to hinder lung cancer-driven BM. Our findings not only suggest lung cancer exhibited tumor specificity in cancer-driven BM model, but also provide ARTS as a promising candidate for clinical treatment of lung cancer-relayed BM.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1528-1538"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575828","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}
Stephanie Goldschmidt, Clifford G Tepper, Jack Goon, Maria Soltero-Rivera, Robert Rebhun, Andrew C Birkeland, Xiao-Jing Wang, Ryan R Davis, Stephenie Y Liu, Iris Rivas, Brian Murphy, Natalia Vapniarsky
{"title":"Spatial Transcriptomic Landscape of Canine Oral Squamous Cell Carcinoma.","authors":"Stephanie Goldschmidt, Clifford G Tepper, Jack Goon, Maria Soltero-Rivera, Robert Rebhun, Andrew C Birkeland, Xiao-Jing Wang, Ryan R Davis, Stephenie Y Liu, Iris Rivas, Brian Murphy, Natalia Vapniarsky","doi":"10.1002/mc.23932","DOIUrl":"10.1002/mc.23932","url":null,"abstract":"<p><p>Canine oral squamous cell carcinoma (COSCC) is the second most common oral tumor in dogs and the most relevant for comparative human trials as a spontaneous large animal model of disease. Historical genomic work has focused primarily on bulk sequencing. The present study describes the complete transcriptomic landscape of COSCC with spatial distinction between the surface tumor, deep invasive tumor, peritumoral dysplastic epithelium, and tumor microenvironment compared to matched normal oral samples. Each region demonstrated distinct molecular signatures. Genes related to epithelial growth factor (EGFR) and epithelial-mesenchymal transformation (EMT) were upregulated in both peritumoral dysplasia and surface cancer. Additionally, the KRAS gene set, KRT17, and SSP1 were enriched in cancer. We identified five genes that represent dysplastic lesion with high potential for malignant transformation (FZD4, GAS1, HACD2, NOG, and SLC39A6). Also, three genes, SFRP4, FZD1, and IL34 represented a specific signature of the invasive portion of the COSCC that should be explored for prognostic value as a biomarker of malignancy. Lastly, we verified the immunomodulatory tumor microenvironment detecting an increase in macrophages and an abundance of IL-10 secretion. The other predominant leukocytes were T-cells, with CD4+ T-cells being the most prevalent. CD4+ T cells expressed transcripts for both stimulatory (Inducible T-cell Co-Stimulator (ICOS) and inhibitory molecules (CTLA4). The observed high CTLA4 suggests that this inhibitory signal may be preventing a robust antitumor immune response. Taken together, this study identified multiple targets to be explored for biomarkers of malignancy, prediction of tumor behavior, and potential targets for development of novel therapies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1415-1428"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317512","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}
Shirley V de Paiva Souza, Andreza Conceição Veras Aguiar, Elizabeth Costa S de Albuquerque, Christina Eich, Luis J Cruz, Pablo Lara, Carla Jorquera-Cordero, Raelle Ferreira Gomes, Regina Célia Monteiro de Paula, Rosemayre S Freire, de Araújo Júnior Raimundo Fernandes de AraújoJúnior
{"title":"M1 Macrophage Extracellular Vesicles and TLR3 Agonist Nanoparticles Down-Regulate Immunosuppression and Metastasis via AKT/TAM in Triple-Negative Breast Cancer.","authors":"Shirley V de Paiva Souza, Andreza Conceição Veras Aguiar, Elizabeth Costa S de Albuquerque, Christina Eich, Luis J Cruz, Pablo Lara, Carla Jorquera-Cordero, Raelle Ferreira Gomes, Regina Célia Monteiro de Paula, Rosemayre S Freire, de Araújo Júnior Raimundo Fernandes de AraújoJúnior","doi":"10.1002/mc.70003","DOIUrl":"10.1002/mc.70003","url":null,"abstract":"<p><p>Metastasis induced by tumor immune escape has been implicated as one of the factors contributing to the aggressiveness of triple-negative breast cancer. Macrophage type 1-derived extracellular vesicles were isolated and combined with PLGA nanoparticles loaded with the TLR3 agonist poly I:C as a therapeutic strategy to investigate their antitumor activity by downregulating tumor immune escape in the tumor microenvironment (TME) of breast cancer in a murine model of orthotopic tumor growth. Tumors were evaluated by qRT-PCR and immunohistochemistry. Cellular uptake and polarization of murine macrophages (RAW 264.7 cells) were analyzed In Vitro by immunofluorescence and flow cytometry, respectively. Furthermore, mouse survival, lymph node involvement, and metastasis were also evaluated. In the animal model, the combination therapy inhibited tumor progression through TME immunomodulation, leading to a reduction in primary tumor size (p < 0.0001) and metastasis, along with an extension in survival of 11 days. Importantly, both innate and adaptive immune responses were enhanced, as indicated by increased CD8 expression (p < 0.0001) and reduced PD-L1 levels in the TME, as well as elevated CD11c expression in lymph nodes (p < 0.0001). Likewise, the combination therapy suppressed tumor progression by reducing AKT1 expression (p < 0.001) and increasing E-cadherin expression (p < 0.01). Based on these findings, the combination therapy functioned as a \"vaccine-like immunomodulatory strategy,\" promoting TME immunomodulation and suppressing metastasis in a murine model of triple-negative breast cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1450-1461"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476105","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":"CDKL3 Targets ATG5 to Exacerbate the Progression of Malignant Melanoma.","authors":"Qi Chen, Wenyuan Yu, Yifei Gu, Shikun Cao, Xiaoming Xie, Lijun Wu","doi":"10.1002/mc.70002","DOIUrl":"10.1002/mc.70002","url":null,"abstract":"<p><p>Melanoma is a type of skin cancer originating from melanocytes with a high risk of gastrointestinal tract metastasis. The abnormal expression of cyclin-dependent kinase-like 3 (CDKL3) is involved in several tumor progression. However, the role of CDKL3 in malignant melanoma has never been reported and remains unknown. In this study, the expression of CDKL3 was revealed using clinical human malignant melanoma tissues and normal skin tissues. The effects of CDKL3 on malignant melanoma cell phenotypes was evaluated in vitro and in vivo via establishing CDKL3 deficiency cell models. Our results indicated that CDKL3 was highly expressed in malignant melanoma tissues, especially in advanced malignant melanoma tissues, in comparison with normal skin tissues. Moreover, CDKL3 knockdown significantly suppressed the proliferation, migration and invasion of malignant melanoma cells, and induced cell apoptosis. The indispensable role of CDKL3 on tumorigenesis was confirmed through in vivo experiments. Finally, we showed that CDKL3 promoted malignant melanoma progression via targeting autophagy related 5 (ATG5). CDKL3 induced melanoma cell autophagy through an ATG5-dependent manner. In conclusion, these results showed the promoting role of CDKL3 in proliferation and migration of malignant melanoma cells. The CDKL3 may be a novel biomarker for malignant melanoma progression and the potential therapeutic target for patients with malignant melanoma.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1462-1472"},"PeriodicalIF":3.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497528","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":"HORMAD1 Polymorphisms Influence Susceptibility to Esophageal Squamous Cell Carcinoma Through Gene-Smoking Interaction.","authors":"Xinying Yue, Zifei Yang, Jialing Ma, Qianqian Su, Miaoxin Pan, Lina Song, Yueping Li, Shasha Liu, Yutong Wu, Jiang Chang","doi":"10.1002/mc.70039","DOIUrl":"https://doi.org/10.1002/mc.70039","url":null,"abstract":"<p><p>Tobacco smoke is a major risk factor for esophageal squamous cell carcinoma (ESCC), yet only a subset of smokers develop this disease, implicating gene-smoking interactions in modulating individual susceptibility. Through integrative transcriptomic analyses of normal and tumor samples from smokers and nonsmokers, we identify four smoke-responsive genes (CXCL14, HORMAD1, WFDC5, and MPZ) as potential contributors to ESCC carcinogenesis. Among these, HORMAD1 is markedly upregulated in ESCC cells upon exposure to cigarette smoke condensate (10 µg/mL), benzo[a]pyrene (3 µM), or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 µM), correlating with activation of error-prone nonhomologous end joining (NHEJ) in response to DNA damage. Notably, smokers with higher HORMAD1 expression levels exhibit enhanced NHEJ but impaired homologous recombination (HR), leading to increased genomic instability. Through a two-stage case-control study involving 5151 ESCC cases and 5963 controls, we identify two regulatory variants of HORMAD1, rs11204679 and rs33924488, significantly associated with ESCC risk through a gene-smoking interaction (p<sub>interaction</sub> = 0.0027). Both variants confer a protective effect among smokers (OR = 0.80, 95% CI: 0.74-0.87, p = 9.58 × 10<sup>-</sup> <sup>8</sup>) but not in nonsmokers (OR = 0.98, 95% CI: 0.90-1.06, p = 0.5950). Mechanistically, the rs11204679 G > C and rs33924488 GA > G- variants attenuate HOXA6 and SOX15 binding at a distal enhancer, respectively, suppressing HORMAD1 expression via long-range chromatin interactions. These findings establish HORMAD1 as a critical mediator of tobacco-related DNA repair dysregulation and a potential biomarker for ESCC risk stratification and precision prevention.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962202","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}