RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma.
RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma.
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RP11-40C6.2通过减弱乙型肝炎病毒相关肝癌中YAP1泛素化来灭活Hippo信号
DOI：
10.14218/jcth.2021.00584
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发表时间：
2023-04-28
影响因子：
3.6
通讯作者：
Tan, Zhongming
中科院分区：
文献类型：
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作者：
Zhuo, Han;Wu, Chen;Tang, Junwei;Zhang, Feihong;Xu, Zhenggang;Sun, Dongwei;Teng, Yue;Tan, Zhongming
由B型肝炎病毒（HBV）感染引起的慢性肝炎是肝细胞癌（HCC）的主要原因。我们研究了致癌HBV感染相关的长非编码RNA在HCC中的作用。对来自癌症基因组图谱（TCGA）的数据进行生物信息学分析以筛选潜在的致癌HBV相关lncRNA。接下来，我们评估了它们在临床样本中的表达，并研究了它们与临床特征的相关性。通过进行体外和体内研究分析了详细的致癌作用。RP 11 -40C6.2是一种HBV感染相关的lncRNA，通过分析TCGA-Liver Hepatocellular Carcinoma数据库进行鉴定。差异表达基因的基因集富集分析和京都基因和基因组百科全书（KEGG）富集分析揭示了RP 11 - 40 C6.2与Hippo信号通路的强关联。RP 11 -40C6.2在HBV感染的HCC患者中过表达。RP 11 -40C6.2的转录与HBV-X蛋白（HBx）的表达呈正相关，而与HBc的表达无相关性。荧光素酶基因报告基因和ChIP分析表明，YAP 1/TAZ/TEADs复合物通过与RP 11 - 40 C6. 2的启动子区域结合，增强RP 11 - 40 C6. 2的转录。RP 11 -40C6.2在HCC细胞系和通过激活YAP 1介导的动物模型中显示致癌特性。体外泛素化实验表明RP 11 -40C6.2可以通过终止YAP 1 s127残基的磷酸化并通过与14-3-3结合进一步终止其降解来促进YAP 1的稳定。RP 11 -40C6.2是HBV感染相关的lncRNA，通过靶向Hippo信号通路发挥其致癌作用。
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. 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. 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. RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.