RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma  

作　　者：Han Zhuo Chen Wu Junwei Tang Feihong Zhang Zhenggang Xu Dongwei Sun Yue Teng Zhongming Tan 

机构地区：[1]Hepatobiliary Center,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [2]General Surgery,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [3]Department of Medical Oncology,Jiangsu Cancer Hospital,Jiangsu Institute of Cancer Research,The Affiliated Cancer Hospital of Nanjing Medical University,Nanjing,Jiangsu,China

出　　处：《Journal of Clinical and Translational Hepatology》2023年第2期323-333,共11页临床与转化肝病杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation (Grant Number 81972675 to T.Z.M.)。

摘　　要：Background and Aims:Chronic hepatitis caused by hepatitis B virus(HBV)infection is a leading cause of hepatocellular carcinoma(HCC).We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC.Methods:Bioinformatics analysis of data from the Cancer Genome Atlas(TCGA)was performed to screen potential oncogenic HBV-related lncRNAs.Next,we assessed their expression in clinical samples and investigated their correlation with clinical characteristics.The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies.Results:RP11-40C6.2,an HBV infection-related lncRNA,was identified by analysis of the TCGA–Liver Hepatocellular Carcinoma database.Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway.RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection.RP11-40C6.2 transcription showed a positive association with HBV-X protein(HBx),but not HBV core protein(HBc)expression,both of which are carcinogenic proteins.Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area.RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1.In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3.Conclusions:RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

关 键 词：Hepatocellular carcinoma Hippo signaling lncRNA YAP1 HBV 

分 类 号：R512.62[医药卫生—内科学] R735.7[医药卫生—临床医学]