The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma
The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma
复制标题
DOI：
10.1016/j.jhep.2013.12.014
复制
发表时间：
2014-05-01
影响因子：
25.7
通讯作者：
Lu, Fengmin
中科院分区：
文献类型：
--
作者：
Li, Xiaojun;Zhang, Jiangbo;Lu, Fengmin
背景和目标：尽管B型肝炎病毒（HBV）整合入人类基因组被认为是肝癌发生的主要原因之一，但其潜在机制仍不清楚。本研究旨在探讨HBV在肝癌组织和癌旁组织中整合的本质差异，并探讨决定HBV整合致癌性的因素。方法：从4项研究中收集1115个HBV整合位点。基于基因本体和KEGG通路数据库，使用大卫进行整合靶向宿主基因（ITG）的功能注释分析。采用阵列表达谱、实时定量PCR和western blot检测反复整合靶基因（RTG）的表达。结果：HBV易于整合在基因区（外显子、内含子和启动子）和基因密集区，UBXN8在8个肝癌细胞系中过表达的生物学后果。功能注释分析显示，与邻近非肿瘤组织中的ITG相比，HCC肿瘤组织中的ITG在与细胞死亡、转录调节、发育和分化以及癌症相关途径的负调控相关的功能方面显著富集。在该分析中鉴定的75个RTG中，32%在HCC组织中异常表达。RTG之一UBXN8是一种新的肿瘤抑制基因，其功能依赖于TP53。结论：HBV整合的致癌性在一定程度上取决于HBV整合靶向宿主基因在HCC中的功能。(C)2013年欧洲肝脏研究协会。Elsevier B.V.出版，保留所有权利。
Background & Aims: Although hepatitis B virus (HBV) integration into the human genome has been considered as one of the major causative factors to hepatocarcinogenesis, the underlying mechanism(s) was still elusive. Here we investigate the essential difference(s) of HBV integration between HCC tumor and adjacent non-tumor tissues and explore the factor(s) that determine the oncogenicity of HBV integration.Methods: 1115 HBV integration sites were collected from four recent studies. Functional annotation analysis of integration targeted host genes (ITGs) was performed using DAVID based on Gene Ontology and KEGG pathway databases. Array-based expression profiles, real-time qPCR and western blot were used to detect the expression of recurrent integration targeted genes (RTGs). The biological consequences of the overexpression of UBXN8 in 8 HCC cell lines were studied in vitro.Results: HBV is prone to integrate in genic regions (exons, introns, and promoters) and gene-dense regions. Functional annotation analysis reveals that, compared to those in adjacent non-tumor tissues, ITGs in HCC tumor tissues were significantly enriched in functional terms related to negative regulation of cell death, transcription regulation, development and differentiation, and cancer related pathways. 32% of the 75 RTGs identified in this analysis expressed abnormally in HCC tissues. UBXN8, one of the RTGs, was identified as a new tumor suppressor candidate which functions in a TP53 dependent manner.Conclusions: The oncogenicity of HBV integration was determined, to some extend by the function of HBV integration targeted host genes in HCC. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.