Hepatitis B Virus Large Surface Antigen Promotes Liver Carcinogenesis by Activating the Src/PI3K/Akt Pathway

Abstract

Of the three envelope glycoproteins encoded by hepatitis B virus (HBV) that are collectively referred to as HBV surface antigen (HBsAg), the large HBsAg (LHBs) glycoprotein is expressed preferentially in HBV-associated hepatocellular carcinoma. LHBs can act as an oncogene in transgenic mice, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of LHBs during HBV-associated hepatocarcinogenesis. LHBs increased tumor formation of hepatoma cells. Moreover, expression of LHBs but not other HBV envelope glycoproteins specifically promoted proliferation of hepatoma and hepatic cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal stimulation of PKCa/Raf1 signaling by LHBs. Proliferation induced by stable LHBs expression was associated with increased G 1 -S cell-cycle progression and apoptosis resistance mediated by Src kinase activation, as established in hepatocellular carcinoma clinical specimens. Importantly, LHBs-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that LHBs promotes tumorigenesis of hepatoma cells by triggering a PKCa/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBVassociated hepatocarcinogenesis. Cancer Res; 71(24); 7547-57. Ó2011 AACR.

Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

“…HCC is a major health problem worldwide, with more than 500,000 new cases currently diagnosed yearly, and our previous investigations have elucidated possible mechanisms for HBV-associated hepatocarcinogenesis (49)(50)(51). We herein demonstrate that RACK1, a scaffold protein highly expressed in normal liver and frequently upregulated in HCC, contributes to the in vitro chemoresistance and in vivo growth of HCC and preferential translation of potent growth and survival factors.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…Further, LHBs can promote carcinogenesis and proliferation of HCC cells through the c-Src/PI3K/Akt pathway, which is trigged by PKC /Raf1 activation. Stable LHB expression in HuH-7 cells also increases G 1 /S cell cycle progression and antiapoptosis via c-Src activation [280].…”

Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB pathway

“…The expression of the genes was quantified by real-time PCR using a Lightcycler480 and SYBR Green system (Roche Diagnostic Systems, Somerville, NJ, USA) following the manufacturer's protocol. 50 Immunoblotting and immunoprecipitation. Protein extraction from cultured cells or tissues, immunoblotting, and immunoprecipitation were carried out as previously described.…”