title: 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 PKCα/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 PKCα/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.
authors: Department of Biochemistry and Molecular Biology, Ministry of Education and Health, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Haiou
authors: H
authors: Liu
authors: Jiejie
authors: J
authors: Xu
authors: Lei
authors: L
authors: Zhou
authors: Xiaojing
authors: X
authors: Yun
authors: Lin
authors: L
authors: Chen
authors: Shanshan
authors: S
authors: Wang
authors: Linlin
authors: L
authors: Sun
authors: Yumei
authors: Y
authors: Wen
authors: Jianxin
authors: J
authors: Gu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D052117:Benzodioxoles; D006514:Hepatitis B Surface Antigens; D019869:Phosphatidylinositol 3-Kinases; D051571:Protein Kinase C-alpha; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D016392:Proto-Oncogene Proteins pp60(c-src); D011799:Quinazolines; C515233:saracatinib