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Genetic control of alternative splicing and its distinct role in colorectal cancer mechanisms

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收录情况： ◇ SCIE ◇ 自然指数

作者：
Ming Zhang[1,2,3] * ; Can Chen[1,2,3] * ; Zequn Lu[1,2,3] * ; Yimin Cai[1,2] ; Yanmin Li[1,2] ; Fuwei Zhang[1,2] ; Yizhuo Liu[1,2] ; Shuoni Chen[1,2] ; Heng Zhang[1,2] ; Shuhui Yang[1,2] ; Hui Gen[1,2] ; Yuan Jiang[1,2] ; Caibo Ning[1,2] ; Jinyu Huang[1,2] ; Wenzhuo Wang[1,2] ; Linyun Fan[1,2] ; Yi Zhang[4] ; Meng Jin[5] ; Jinxin Han[6] ; Zhen Xiong[6] ; Ming Cai[6] ; Jiuyang Liu[7] ; Chaoqun Huang[7] ; Xiaojun Yang[7] ; Bin Xu[8] ; Heng Li[9] ; Bin Li[1,2] ; Xu Zu[10] ; Yongchang Wei[11] ; Ying Zhu[1,2] ; Jianbo Tian[1,2,3,*1] ; Xiaoping Miao[1,2,3,12,13,*2] ;
单位： [1]Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China [2]Department ofGastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, WuhanUniversity, Wuhan, China [3]Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan,China [4]Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China [5]Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China [6]Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University ofScience and Technology, Wuhan, China [7]Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University,Wuhan University, Wuhan, China [8]Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China [9]Department of Urology,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China [10]Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China [11]Department ofGastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China [12]Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China [13]Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
出处：
DOI： 10.1053/j.gastro.2023.07.019
ISSN：

关键词： Alternative Splicing sQTLs Functional PRS PRMT7 Arginine Methylation

摘要：
Dysregulation of alternative splicing is implicated in many human diseases and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms.Firstly, we performed a comprehensive sQTL analysis to identify genetic variants that control mRNA splicing across 33 cancer types from TCGA and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multiethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes.The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. Besides, functionally informed polygenetic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese populations (OR=1.20, 95% CI=1.12-1.29, P=8.82×10-7) and European populations (OR=1.11, 95% CI=1.07-1.16, P=1.13×10-7). rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RBP PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors, compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells.Our study provide an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk, serving as biomarkers and therapeutic targets.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.

基金：
Distinguished Young Scholars of China (NSFC- Q8 81925032) and Key Program of National Natural Science Foundation of China (NSFC-82130098) to Xiaoping Miao; the Program of National Natural Science Foundation of China (NSFC-82103929, NSFC-82273713) and Young Elite Scientists Sponsorship Program by CAST (2022QNRC001) to Jianbo Tian; the Fundamental Research Funds for the Central Universities (2042022rc0026, 2042023kf1005) for Xiaoping Miao; Fundamental Research Funds for the Central Universities (WHU: 2042022kf1205), Knowledge Innovation Program of Wuhan (whkxjsj011) and Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (ZNJC202207) to Jianbo Tian; Youth Program of National Natural Science Foundation of China (NSFC-82003547), Program of Health Commission of Hubei Province (WJ2023M045) and Fundamental Research Funds for the Central Universities (WHU: 2042022kf1031) to Ying Zhu.
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
JCR分区：
出版当年[2021]版：
Q1 GASTROENTEROLOGY & HEPATOLOGY
最新[2024]版：
Q1 GASTROENTEROLOGY & HEPATOLOGY

影响因子： 最新[2024版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者单位： [1]Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China [2]Department ofGastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, WuhanUniversity, Wuhan, China [3]Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan,China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China [2]Department ofGastrointestinal Oncology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, WuhanUniversity, Wuhan, China [3]Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan,China [12]Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China [13]Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China [*1]Department of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan, 430071, China. [*2]Department of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University.Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan, 430071, China.
推荐引用方式(GB/T 7714)：
Ming Zhang,Can Chen,Zequn Lu,et al.Genetic control of alternative splicing and its distinct role in colorectal cancer mechanisms[J].GASTROENTEROLOGY.2023,165(5):1151-1167.doi:10.1053/j.gastro.2023.07.019.
APA：
Ming Zhang,Can Chen,Zequn Lu,Yimin Cai,Yanmin Li...&Xiaoping Miao.(2023).Genetic control of alternative splicing and its distinct role in colorectal cancer mechanisms.GASTROENTEROLOGY,165,(5)
MLA：
Ming Zhang,et al."Genetic control of alternative splicing and its distinct role in colorectal cancer mechanisms".GASTROENTEROLOGY 165..5(2023):1151-1167

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