有针对性的宿主基因的功能确定HBV整合在肝癌的致癌性

StephenW

The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma

    Xiaojun Li a, 1,
    Jiangbo Zhang a, 1,
    Ziwei Yang a,
    Jingting Kang a,
    Suzhen Jiang b,
    Ting Zhang a,
    Tingting Chen a,
    Meng Li a,
    Xiangmei Chen a, Corresponding author contact information, E-mail the corresponding author,
    Malcolm A. McCrae c,
    Hui Zhuang a,
    Fengmin Lu a, Corresponding author contact information, E-mail the corresponding author

    a Department of Microbiology& Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P. R. China
    b Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, P. R. China
    c The Pirbright Institute, Pirbright, UK


Abstract
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) 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) were 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 are 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.

StephenW

摘要
背景及目的

虽然B型肝炎病毒（HBV）整合到人基因组已被认为是主要的致病因素，以肝癌中的一个，底层机制（S ）仍然是难以捉摸的。在这里，我们探讨肝癌肿瘤与邻近非肿瘤组织之间的HBV整合的本质区别（ S）和探索因子（ S）确定HBV整合的致癌性。
方法

1115 HBV整合位点是从近四年的研究收集。使用DAVID基于基因本体论和KEGG通路数据库进行了整合目标主机基因功能注释分析（ ITGS ） 。基于阵列的表达谱，实时定量PCR和Western blot分别检测复发整合靶基因（ RTGS）的表达。 UBXN8在8 HCC细胞系中过表达的生物学后果进行了研究体外。
结果

乙肝病毒很容易在基因区域（外显子，内含子和启动子）和基因密集区域整合。功能注释分析表明，相比那些在旁非肿瘤组织，在肝癌肿瘤组织ITGS均显著的相关性细胞死亡的负调控，转录调控，发育和分化，与癌症相关通路功能方面更加丰富。在此分析中确定的75台RTG 32％的HCC组织中异常表达。 UBXN8 ，即时支付结算系统之一，被确定为一个新的抑癌候选的TP53的依赖性它的功能。
结论

HBV整合的致癌性是确定的，在一定程度上由乙肝病毒整合的目标函数在肝癌的宿主基因。