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



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).
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Dan
D
Liu
Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, P.R. China.
Lei
L
Cui
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Yuan
Y
Wang
Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan, P.R. China.
Guifang
G
Yang
Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, P.R. China.
Jing
J
He
Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, P.R. China.
Ruidong
R
Hao
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Chengpeng
C
Fan
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Mengmeng
M
Qu
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Zhepeng
Z
Liu
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Min
M
Wang
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Lang
L
Chen
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Hui
H
Li
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, P.R. China.
Deyin
D
Guo
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006512:Hepatitis B Core Antigens / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2