RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells  

作　　者：Pascale Palassin Marion Lapierre Sandrine Bonnet Marie-Jeanne Pillaire Balázs Győrffy Catherine Teyssier Stéphan Jalaguier Jean-Sébastien Hoffmann Vincent Cavaillès Audrey Castet-Nicolas 

机构地区：[1]IRCM,Institut de Recherche en Cancérologie de Montpellier,INSERM,U1194,Institut Régional du Cancer de Montpellier,Universitéde Montpellier,Montpellier 34298,France [2]Institut de Pharmacologie et de Biologie Structurale,IPBS,Universitéde Toulouse,CNRS,UPS,Toulouse 31077,France. [3]Department of Bioinformatics,Semmelweis University and TTK Lendület Cancer Biomarker Research Group,Budapest H-1117,Hungary [4]Laboratoire de pathologie,Laboratoire d’excellence Toulouse Cancer,Institut Universitaire du Cancer-Toulouse,Oncopole,Toulouse 31059,France [5]Département de Pharmacie Clinique,Centre Hospitalo-Universitaire Montpellier,Montpellier 34295,France. [6]Unitéde Formation et de Recherche des Sciences Pharmaceutiques et Biologiques,Montpellier 34090,France.

出　　处：《Cancer Drug Resistance》2022年第2期401-414,共14页癌症耐药（英文）

摘　　要：Aim:The transcription factor RIP140(receptor interacting protein of 140 kDa)is involved in intestinal tumorigenesis.It plays a role in the control of microsatellite instability(MSI),through the regulation of MSH2 and MSH6 gene expression.The aim of this study was to explore its effect on the expression of POLK,the gene encoding the specialized translesion synthesis(TLS)DNA polymeraseκknown to perform accurate DNA synthesis at microsatellites.Methods:Different mouse models and engineered human colorectal cancer(CRC)cell lines were used to analyze by RT-qPCR,while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression.Published DNA microarray datasets were reanalyzed.The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results:RIP140 positively regulates,at the transcriptional level,the expression of the POLK gene,and this effect involves,at least partly,the p53 tumor suppressor.In different cohorts of CRC biopsies(with or without MSI),a strong positive correlation was observed between RIP140 and POLK gene expression.In connection with its effect on POLK levels and the TLS function of this polymerase,the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene.Finally,the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK,thus strengthening the functional link between the two genes in human CRC.Conclusion:The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability,and more generally to the control of genome integrity.

关 键 词：Colorectal cancer genome stability translesion DNA synthesis polymerase Pol Kappa RIP140 

分 类 号：R73[医药卫生—肿瘤]