Regulatory factor X5 promotes hepatocellular carcinoma progression by transactivating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta and suppressing apoptosis  

作　　者：Dong-Bo Chen Yang-Jing Zhao Xue-Yan Wang Wei-Jia Liao Pu Chen Kang-Jian Deng Xu Cong Ran Fei Xu Wu Qi-Xiang Shao Lai Wei Xing-Wang Xie Hong-Song Chen 

机构地区：[1]Peking University People's Hospital,Peki叩University Hepatology Institute,Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease,Beiji叩100044,China [2]Department of Immunology,The Key Laboratory of Laboratory Medicine of Jiangsu Province,School of Medicine,Jiangsu University,Zhenjiang,Jiangsu 212013,China [3]Laboratory of Hepatobiliary and Pancreatic Surgery,Affiliated Hospital of Guilin Medical University,Guilin,Guangxi 541001,China [4]Center of Excellence,Becton Dickinson Biosciences,Beijing 100176,China

出　　处：《Chinese Medical Journal》2019年第13期1572-1581,共10页中华医学杂志（英文版）

基　　金：grants from the National Natural Science Foundation of China(No.81201569 and No.81541151);the Beijing Natural Science Foundation(No.7132186);the National Key Sci-Tech Special Project of China(No.2018ZX10302207,No.2017ZX10203202).

摘　　要：Background:Our previous studies have shown that regulatory factor X5(RFX5),a classical transcription regulator of MHCⅡ genes,was obviously overexpressed in hepatocellular carcinoma(HCC)tumors.However,the role of RFX5 in the carcinogenesis and progress of HCC remains unknown.This study aimed to reveal its biological significance and the underlying mechanism in HCC.Methods:RFX5 mRNA expression level and copy number variation in HCC tumors and cell lines were determined by analyzing deposited data sets in the Cancer Genome Atlas and Gene Expression Omnibus database.The biological significance of RFX5 in HCC was investigated by monitoring the colony formation and subcutaneous tumor growth capacity when RFX5 was silenced with lentiviral short hairpin RNA and CRISPR7Cas9 system in HCC cell lines.The downstream gene transcriptionally activated by RFX5 in HCC cells was determined by chromatin immunoprecipitation and luciferase reporter assay.The involvement of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta(YWHAQ)in HCC development was further determined by performing colony formation rescue assay and subcutaneous tumor growth rescue experiment.The association of YWHAQ with recurrence-free survival of patients with HCC was assessed by Kaplan-Meier analysis.Moreover,apoptosis level and the protein level of p53 pathway were determined to reveal the mechanism of RFX5 in driving HCC development.Results:RFX5 was amplified and highly overexpressed in HCC tumor tissues compared with the corresponding non-tumor tissues.The mRNA expression level of RFX5 was significantly correlated with its DNA copy number(r=0.4,P<0.001).Functional study demonstrated that RFX5 was required for both clonogenic forming in vitro and subcutaneous tumor growth in vivo of HCC cells.Further study identified YWHAQ,namely 14-3-3 tau,as a key downstream transcriptional target gene of RFX5,which was tightly regulated by RFX5 in HCC.Moreover,overexpression of YWHAQ largely rescued the clonogenic growth of HCC cells that was sup

关 键 词：HEPATOCELLULAR carcinoma TRANSCRIPTION factor APOPTOSIS P53 

分 类 号：R[医药卫生]