乙肝e抗原及其前体通过与NUMB相互作用并降低p53活性促进肝细

StephenW

Viral Hepatitis
Hepatitis B e antigen and its precursors promote the progress of hepatocellular carcinoma by interacting with NUMB and decreasing p53 activity
Authors

    First published: 26 May 2016Full publication history
    DOI: 10.1002/hep.28594View/save citation
    Cited by: 0 articles Check for new citations
    Article has an altmetric score of 5
    Funding Information

    Potential conflict of interest: Nothing to report.

    Supported by the National Science Foundation of China (81572006, 81130083, 81501758, and 31221061) and by Hubei Province's Outstanding Medical Academic Leader Program and Innovation Team (2015CFA009, to D.G.).

Abstract

Hepatitis B viral infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Although several viral factors have been identified that may increase the risk for HCC development, the molecular mechanisms leading to the transformation of normal hepatocytes into cancer cells remain elusive. In this study, we demonstrated that the intracellular hepatitis B e antigen (HBeAg) and its precore precursors, but not their homologous core protein, could associate with NUMB and thereby impair the stability and transcriptional activity of tumor suppressor p53. HBeAg and its precursors could disrupt p53-NUMB and HDM2-NUMB interactions and tricomplex p53-HDM2-NUMB formation, inhibit the acetylation and translocation of p53 from cytosol to the nucleus, promote HDM2-mediated ubiquitination and degradation of p53, and suppress p53-dependent apoptosis. A xenograft tumorigenicity assay showed that expression of HBeAg and its precursors promoted carcinogenesis in a mouse model. Immunohistochemical analysis of the bioptic liver samples of HCC patients revealed that HBeAg positivity was associated with reduced transcriptional activity of p53. Taken together, the results suggest a role of intracellular HBeAg and its precursors in HCC development. Conclusion: HBeAg and its precursors promote HDM2-mediated degradation and impair transcriptional activity of p53 by interacting with NUMB, consequently contributing to HCC development. (Hepatology 2016;64:390-404)

StephenW

病毒性肝炎
乙肝e抗原及其前体通过与NUMB相互作用并降低p53活性促进肝细胞癌的进展
作者

    首先公布：5月26日公布2016Full历史
    ：10.1002 / hep.28594View /保存引文
    引述：0物品检查新引文
    制品具有为5 altmetric得分
    资金的信息

    潜在的利益冲突：无报告。

    由中国（81572006，81130083，81501758，31221061和）的美国国家科学基金会和湖北省优秀医学学科带头人计划和创新团队（2015CFA009，到D.G.）支持。

抽象

乙型肝炎病毒感染是世界范围内肝细胞癌（HCC）的主要原因之一。虽然几种病毒因素已被确定，可能会增加肝癌发展的风险，从而导致正常肝细胞的转化成癌细胞的分子机制仍难以捉摸。在这项研究中，我们表明，细胞内的乙型肝炎e抗原（HBeAg）及其前核心前体，而不是它们的同源核心蛋白，可以与NUMB关联，并从而削弱肿瘤抑制基因p53的稳定性和转录活性。大三阳及其前体可能破坏P53-NUMB和HDM2麻木相互作用和tricomplex P53-HDM2麻木形成，抑制从胞浆乙酰化和p53易位到细胞核，促进HDM2介导的泛素化和p53的降解，并抑制p53-依赖的细胞凋亡。异种移植瘤性试验表明，HBeAg和及其前体的表达在小鼠模型中促进癌变。 HCC患者的活检肝脏样品的免疫组织化学分析显示，e抗原阳性率与p53的降低转录活性相关联。两者合计，结果表明细胞内HBeAg和其在HCC发展前体的作用。结论：HBeAg和它的前体促进HDM2介导的降解，并通过与NUMB互动，从而促进肝癌发展的影响p53的转录活性。 （2016年肝病; 64：390-404）