HBV e antigen and its precursors promote the progress of HCC by interacting with NUMB and decreasing p53 activity.

Hepatitis B virus (HBV) 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 HBV 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 tri-complex 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. Xenograft tumorigenicity assay showed that the 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.HBeAg and its precursors promote HDM2-mediated degradation and impair transcriptional activity of p53 via interacting with NUMB, consequently contributing to the HCC development. This article is protected by copyright. All rights reserved.
Hepatology Apr. 22, 2016; 0(0); [PUBMED:27106262]
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