Hepatitis B Virus Large Surface Antigen Promotes Tumorigenesis of Human Hepatocellular Carcinoma Cells through Activating Src/PI3K/Akt Pathway

There are three hepatitis B virus (HBV) envelope glycoproteins collectively known as hepatitis B virus surface antigen (HBsAg), including the large (LHBs), middle (MHBs), and small (SHBs) surface proteins. Among them, LHBs has been retained in a large proportion of liver tissues in HBV-associated hepatocellular carcinoma (HCC) patients and shown oncogenic function in transgenic mice. However, the concrete functions of LHBs in carcinogenesis of HBV-associated HCC remain elusive. In this study, we investigated the molecular and functional roles of LHBs in HBV-associated hepatocarcinogenesis. Tumor xenograft experimental data in nude mice indicated that LHBS increased tumor formation of hepatoma cells. Moreover, LHBs expression, but neither MHBs nor SHBs expression could promote colony formation and cellular proliferation of hepatoma and hepatic cells in vitro. These effects of LHBs on hepatoma cells were due to Src/PI3K/Akt signal instigation mediated by PKC /Raf1 activation. Furthermore, stable LHBs expression could promote cellular proliferation, elevate colony formation, induce G1-S cell cycle progression, and confer apoptosis resistance via Src tyrosine kinase activation in hepatoma cells. Specific Src inhibitor Saracatinib administration could reverse cellular proliferation instigation and tumor formation promotion conferred by LHBs expression in vitro and in vivo. Finally, the positive correlations between increased staining of pSrc(Y416), pAkt(S473), and proliferative marker Ki67 with LHBs expression were observed in hepatoma tissues from HCC patients. In conclusion, our results propose that LHBs could promote tumorigenesis of hepatoma cells dependent on PKC /Raf1/Src/PI3K/Akt signal activation, which reveals a novel insight into the underlying mechanisms for HBV-associated hepatocarcinogenesis. on April 11, 2017. © 2011 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 12, 2011; DOI: 10.1158/0008-5472.CAN-11-2260