Carcinogenesis最新文献

{"title":"Chemoresistance and Immune Evasion in HCC: The Role of miRNA-425-5p.","authors":"Xinghe Pan, Junliang Liu, Yitong Zhang, Chenglin Sun, You Li","doi":"10.1093/carcin/bgaf012","DOIUrl":"https://doi.org/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 (TEM) and nanoparticle tracking analysis (NTA). 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 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":"2025-03-10","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}

{"title":"Manuscript Smoking Behavior-related Genetic Variants and Lung Cancer Risk in Japanese: an Assessment by Mediation Analysis.","authors":"Sayaka Yamamoto, Yuriko N Koyanagi, Yuji Iwashita, Tomohiro Shinozaki, Yutaka Fujiwara, Noriaki Sakakura, Megumi Hara, Yuichiro Nishida, Jun Otonari, Hiroaki Ikezaki, Shiroh Tanoue, Chihaya Koriyama, Yumiko Kasugai, Isao Oze, Teruhide Koyama, Satomi Tomida, Nobuaki Michihata, Yohko Nakamura, Sadao Suzuki, Hiroko Nakagawa-Senda, Mako Nagayoshi, Yoko Kubo, Yasufumi Kato, Kenji Wakai, Takeshi Watanabe, Masashi Ishizu, Naoyuki Takashima, Aya Kadota, Yukihide Momozawa, Masahiro Nakatochi, Takashi Tamura, Akio Niimi, Hidemi Ito, Keitaro Matsuo","doi":"10.1093/carcin/bgaf011","DOIUrl":"https://doi.org/10.1093/carcin/bgaf011","url":null,"abstract":"<p><p>Cigarette smoking is one of the most important risk factors for lung cancer. Genetic studies have shown that smoking behavior-related genetic variants are directly associated with lung cancer, independent of smoking behavior, mainly in European populations. A recent genome-wide association study in Japan identified five loci associated with the number of cigarettes smoked per day. This study aimed to evaluate whether these loci are associated with lung cancer risk directly or indirectly through changing smoking behavior. Here, we conducted a case-control study (1427 cases and 5595 controls) and a prospective cohort study (128 incident cases in 10 520 subjects). Using mediation analysis, we decomposed the total effect of the lead single nucleotide polymorphism (SNP) at each locus on lung cancer risk into direct and indirect effects. The results of the two studies were pooled using a random-effects model to estimate summary relative risks (RRs) and their 95% confidence intervals (CIs). Two studies showed that: (a) rs78277894 (EPHX2-CLU, G>A) had a protective direct effect (RR 0.84; 95% CI 0.77-0.93) on lung cancer risk; and (b) rs56129017 (CYP2A6, C>T) had carcinogenic direct and indirect effects on lung cancer risk (RR 1.26; 95% CI 1.15-1.39 and RR 1.01; 95% CI 1.00-1.01, respectively). This mediation analysis revealed that two smoking behavior-related SNPs, EPHX2-CLU rs78277894 and CYP2A6 rs56129017, were associated with lung cancer risk through pathways independent of changing smoking behavior. Our findings may contribute to our understanding of lung carcinogenesis pathways that cannot be addressed by changes in smoking behavior.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584838","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":"Olfactomedin 4 promotes gastric cancer cell G2/M progression and serves as a therapeutic target in gastric adenocarcinoma.","authors":"Wenli Liu, Hongzhen Li, Istvan Botos, Chutima Kumkhaek, Jianqiong Zhu, Griffin P Rodgers","doi":"10.1093/carcin/bgaf010","DOIUrl":"10.1093/carcin/bgaf010","url":null,"abstract":"<p><p>Olfactomedin 4 (OLFM4) is a member of the olfactomedin domain-containing olfactomedin glycoprotein family and plays important roles in innate immunity, inflammation, and cancer. It exhibits increased expression in gastric cancer patient tissues and has been shown to regulate proliferation and apoptosis in gastric cancer cells. However, the molecular mechanism(s) underlying OLFM4's role in gastric cancer remain unknown. In this study, we found that OLFM4 knock-down significantly inhibited YCC3 gastric cancer cell proliferation and induced G2/M cell cycle arrest. Yeast two-hybridization screening revealed that OLFM4 directly interacts with cyclin B1 interacting protein 1 (CCNB1IP1), an E3 ubiquitin protein ligase. In YCC3 cells, OLFM4 co-immunoprecipitated and colocalized with CCNB1IP1, and underwent cell cycle phase-specific nucleo-cytoplasmic shuttling. OLFM4 knockdown decreased both cyclin B1 protein levels and CDK1 activity in YCC3 cells. Screening of a cohort of OLFM4-targeted microRNAs (miRNAs) for their impact on cell proliferation identified several that significantly downregulated OLFM4 protein levels and inhibited YCC3 cell proliferation in vitro. Rescue experiments demonstrated that these miRNAs' inhibitory effect on cell proliferation was partially related to their downregulation of OLFM4. When three of these miRNAs were individually administered intratumorally to nude mice bearing YCC3 cell xenografts, tumor growth was significantly inhibited when compared with tumors treated with a negative control miRNA. These results suggest that OLFM4 promotes cell cycle progression and cell proliferation in gastric cancer cells and may have utility as a therapeutic target in gastric adenocarcinoma.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582186","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":"LncRNA MEG3 Suppresses Prostate Cancer Progression by Mediating Macrophage Polarization via the miR-148a-3p/ARRDC3 Signaling Axis.","authors":"Jinguang Luo, Huaixiang Tao, Long Chen, Hao Hu, Likai Mao, Han Guan","doi":"10.1093/carcin/bgaf009","DOIUrl":"https://doi.org/10.1093/carcin/bgaf009","url":null,"abstract":"<p><p>Long-chain non-coding RNA (LncRNA) MEG3 significantly influences tumor microenvironment (TME) dynamics and macrophage polarization. However, its specific involvement in prostate cancer (PCa) progression remains unclear. MEG3 exhibited low expression in PCa, and immune infiltration analysis revealed a positive association with M1 macrophages infiltration and a negative association with M2 macrophages infiltration. Immunohistochemical analysis demonstrated increased MEG3 levels, corresponding with upregulated INOS (an M1 marker) and downregulated CD163 (an M2 marker). MEG3 expression was markedly elevated in LPS-induced M1 macrophages and notably reduced in IL-4-induced M2 macrophages. The overexpression of MEG3 significantly enhanced M1 macrophages polarization while suppressing M2 macrophages polarization. Using an online database and a dual luciferase reporter assay, miR-148a-3p was identified as a downstream target of MEG3. Reduced miR-148a-3p expression was observed in LPS-induced M1 macrophages, while an increase was noted in IL-4-induced M2 macrophages. Moreover, MEG3 overexpression's impact on macrophage polarization was nullified following miR-148a-3p mimic transfection. ARRDC3 was validated as a downstream target of miR-148a-3p. The upregulation of ARRDC3 triggered by MEG3 overexpression was effectively suppressed by miR-148a-3p mimics. Additionally, Knockdown of ARRDC3 effectively counteracted the MEG3 overexpression-induced increase in M1 macrophages polarization while simultaneously mitigating the reduction in M2 macrophages polarization. Collectively, MEG3 exhibits reduced expression in PCa and correlates with macrophage infiltration and polarization. Specifically, it drives M1 macrophages polarization while suppressing M2 macrophages polarization via the miR-148a-3p/ARRDC3 axis, thereby impeding tumor immune evasion and restricting PCa progression.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555779","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":"Reactions of [13C]-Labelled Tobacco Smoke with DNA to Generate Selected Adducts Formed Without Metabolic Activation.","authors":"Mei-Kuen Tang, Trevor Ostlund, Nour F Dameh, Aleksandra Alcheva, Jerry D Cohen, Adrian D Hegeman, Steven G Carmella, Irina Stepanov, Stephen S Hecht","doi":"10.1093/carcin/bgaf008","DOIUrl":"https://doi.org/10.1093/carcin/bgaf008","url":null,"abstract":"<p><p>DNA adducts are central in the carcinogenic process because they can cause miscoding leading to permanent mutations in important genes involved in carcinogenesis. While it is known that tobacco smoking leads to increased levels of multiple DNA adducts, most DNA adducts detected to date in humans cannot be explicitly attributed to smoking but instead have various possible exogenous and endogenous sources. We plan to probe the tobacco source of DNA adducts by providing carbon-13 labelled ([13C]-labelled) cigarettes to smokers and analyzing [13C]-labelled DNA adducts in their oral cells to determine which adducts arise from smoking. Prior to conducting studies in humans, we first report here proof-of-principle machine smoking experiments to evaluate carbon isotopologues of (a) selected carbonyls and (b) DNA adducts resulting from direct exposure of cigarette smoke vapor-phase to calf-thymus DNA. The smoke of the study cigarettes, made from a 50:50 mixture of [13C]-labelled tobacco and a popular commercial tobacco, yielded similar concentrations of carbonyl compounds and their respective DNA adducts compared with the smoke of 1R6F reference cigarettes and the popular brand of cigarettes. We detected [13C]-isotopologues of DNA adducts such as 1,N6-etheno-dA, (8R/S)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dG), and (6S,8S and 6R,8R)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)-γ-OH-Cro-dG and (6R,8R)-γ-OH-Cro-dG], proving that they have a direct source from tobacco smoke and providing important new insights regarding their mechanisms of formation. These unique results form the basis for further studies in cell culture and in cigarette smokers to establish how carcinogens in tobacco smoke cause DNA adduct formation.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555943","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":"TNBC molecular subtypes and potential detection targets for biological therapy indications.","authors":"Yanchuan Zhang, Qinghua Li, Jie Lan, Guojing Xie, Guangjie Zhang, Junhao Cui, Ping Leng, Yingshuang Wang","doi":"10.1093/carcin/bgaf006","DOIUrl":"https://doi.org/10.1093/carcin/bgaf006","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor prognosis. While chemotherapy remains the conventional treatment approach, its efficacy is limited and often accompanied by significant toxicity. Advances in precision-targeted therapies have expanded treatment options for TNBC, including immunotherapy, poly (ADP-ribose) polymerase inhibitors, androgen receptor inhibitors, cell cycle-dependent kinase inhibitors, and signaling pathway inhibitors. However, the heterogeneous nature of TNBC contributes to variations in treatment outcomes, underscoring the importance of identifying intrinsic molecular subtypes for personalized therapy. Additionally, due to patient-specific variability, the therapeutic response to targeted treatments is inconsistent. This highlights the need to strategize patients based on potential therapeutic targets for targeted drugs to optimize treatment strategies. This review summarizes the classification strategies and immunohistochemical (IHC) biomarkers for TNBC subtypes, along with potential targets for identifying indications for targeted drug therapy. These insights aim to support the development of personalized treatment approaches for TNBC patients.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467166","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":"Yes-associated protein (YAP) plays oncogenic roles in human sporadic colorectal adenomas.","authors":"Lei Fan, Xinyi Guo, Mary K Washington, Jiajun Shi, Reid M Ness, Qi Liu, Wanqing Wen, Shuya Huang, Xiao Liu, Qiuyin Cai, Wei Zheng, Robert J Coffey, Martha J Shrubsole, Timothy Su","doi":"10.1093/carcin/bgaf007","DOIUrl":"https://doi.org/10.1093/carcin/bgaf007","url":null,"abstract":"<p><p>The role of Hippo-YAP in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r=0.53, P<0.0001) and nuclear β-catenin (r=0.26, P=0.0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P=0.05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR=12.62, 95% CI=4.57-34.86, P trend<0.001), which persisted after adjusting for covariates and biomarkers (OR=12.31, 95% CI=3.78-40.10, P trend<0.0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced vs. non-advanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR=16.82, 95% CI=4.41-64.08, P<0.0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467167","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":"Dysregulation of G6PD by HPV E6 exacerbates cervical cancer by activating the STAT3/PLOD2 pathway.","authors":"Jie Zhang, Wei Dong, Qin Yang, Li-Na Liu, Xi-Lun Cai, Dan Wang, Guo-Ji Yan, Yan-Bin Xiyang, Tao Hu, Jie Zhang","doi":"10.1093/carcin/bgaf005","DOIUrl":"https://doi.org/10.1093/carcin/bgaf005","url":null,"abstract":"<p><p>High-risk human papillomavirus (HPV) infection is strongly linked to the initiation and progression of cervical cancer, yet the precise molecular mechanisms involved remain partially understood. This investigation examined differential protein expression profiles in various cohorts, including healthy controls and HPV-positive cervical cancer patients with different expression levels of glucose-6-phosphate dehydrogenase (G6PD), shedding light on the dysregulation of oncogenic proteins by HPV. Proteomic analysis of cervical tissues revealed specific protein signatures, indicating significant upregulation of HPV E6, G6PD, STAT3, phosphorylated STAT3, and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in HPV-infected cervical cancer tissues and cell lines. Functional experiments, involving the manipulation of G6PD and STAT3 activities in cervical cancer cells with HPV E6 modulation, demonstrated that dysregulated G6PD enhanced cell proliferation, migration, and invasion while suppressing apoptosis, primarily through the STAT3/PLOD2 pathway. Integrating these findings with the existing literature underscores the role of G6PD as an oncogene, potentially under STAT3 regulation, and highlights the role of PLOD2 as a pivotal factor in cervical cancer progression. This study also proposed a mechanism in which HPV E6-induced dysregulation of G6PD activates the STAT3-PLOD2 axis to promote cervical cancer progression. Understanding the intricate interplay between HPV E6, G6PD, STAT3, and PLOD2 offers valuable insights into the molecular landscape of cervical cancer. These findings may pave the way for targeted therapeutic approaches aimed at disrupting this axis to mitigate the progression of cervical cancer.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405741","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":"Role of the nucleotide excision repair function of CETN2 in the inhibition of the sensitivity of hepatocellular carcinoma cells to oxaliplatin.","authors":"Hengcheng Tang, Huaduan Zi, Donghu Zhou, Yanmeng Li, Xiaojin Li, Zhibin Chen, Qianyu Zhu, Qin Ouyang, Pingping He, Sisi Chen, Yanling Li, Jiang Long, Jian Huang","doi":"10.1093/carcin/bgaf003","DOIUrl":"https://doi.org/10.1093/carcin/bgaf003","url":null,"abstract":"<p><p>Resistance to platinum-based chemotherapy agents like oxaliplatin (OXA) poses significant challenges in the treatment of cancers such as hepatocellular carcinoma (HCC). Centrin 2 (CETN2), which functions in nucleotide excision repair (NER) of DNA damage, is overexpressed in HCC. We investigated the potential role of CETN2 in modulating the sensitivity of HCC cells to OXA. CETN2 expression correlated with decreased OXA sensitivity in Huh7 and Hep3B HCC cell lines. CETN2 forms a complex with XPC, which is crucial for the initial DNA damage recognition in NER, thereby enhancing NER and reducing the efficacy of OXA. siRNA-mediated knockdown of CETN2 increased OXA-induced cytotoxicity and apoptosis, confirming its role in chemoresistance. Moreover, overexpression of CETN2 inhibited OXA-induced DNA damage, an effect partially reversed by XPC knockdown. Our findings highlight CETN2 as a potential biomarker and therapeutic target in overcoming OXA resistance in HCC and suggest the possibility for CETN2 inhibitors in enhancing chemotherapeutic efficacy in the treatment of HCC.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405744","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":"Integrative functional screen of genomic loci uncovers CCND2 and its genetic regulatory mechanism in colorectal cancer development.","authors":"Bin Li, Mei Wu, Hui Geng, Yan Li, Zhirui Chen, Zequn Lu, Xu Chen, Qiuhong Wang, Shuxin Song, Xiangpan Li, Xu Zhu, Yongchang Wei, Ying Zhu, Xiaoping Miao, Jianbo Tian, Jiuyang Liu, Chaoqun Huang, Xiaojun Yang","doi":"10.1093/carcin/bgae078","DOIUrl":"10.1093/carcin/bgae078","url":null,"abstract":"<p><p>Although genome-wide association studies have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often remain elusive. Recently, the genomic locus 12p13.32, with the tag single-nucleotide polymorphism rs10774214, was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here, we applied a high-throughput RNA interference approach in CRC cell lines to interrogate the function of genes in this genomic region. Multiple genes were found to affect cell functions, with CCND2 having the most significant effect as an oncogene. Moreover, overexpressed CCND2 could promote CRC cell proliferation. Subsequently, by integrating a fine-mapping analysis and multi-ancestry large-scale population cohorts consisting of 14 358 CRC cases and 34 251 healthy controls, we identified a regulatory variant rs4477507-T that contributed to an increased CRC risk in populations from China (odds ratio = 1.16, 95% confidence interval = 1.11-1.22, P = 4.45 × 10-10) and Europe (odds ratio = 1.17, 95% confidence interval = 1.12-1.21, P = 1.65 × 10-14). Functional characterization of the variant demonstrated that it could act as an allele-specific enhancer to distally facilitate the expression of CCND2 mediated by the transcription factor TEAD4. Overall, our study underscores the essential role of CCND2 in CRC development and delineates its regulatory mechanism mediated by rs4477507, establishing an epidemiological and biological link between genetic variation and CRC pathogenesis.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827500","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}