title: Oncogenic circuit constituted by Ser31-HBx and Akt increases risks of chronic hepatitis and hepatocellular carcinoma.
abstract: The X protein of hepatitis B virus (HBx) has been specifically implicated in the development of hepatocellular carcinoma (HCC). Clinical associations of HBx isoforms with chronic hepatitis and HCC have not been well studied. HBx has two roles in liver cells, namely pro-apoptotic and anti-apoptotic. In this report, we examined the role of Ser31-HBx in HCC and chronic hepatitis. Using the case-control study, we determined risks of chronic hepatitis and HCC conferred by hepatitis B virus (HBV) containing Ser31-HBx that was phosphorylated by Akt. Ser31-HBx isoforms conferred 3.23-fold risk of HCC in male and 3.36-fold risk in female. Ser31 isoforms were associated with 3.12-fold risk of chronic hepatitis and 3.43-fold risk of cirrhosis and also associated with higher HBV viral load and replication efficiency and lower rate of HBe loss. To determine the mechanism, we found that Ser31-HBx constituted an oncogenic circuit with Akt and cooperated with ras to transform NIH3T3 cells in contrast to non-Ser31-HBxs that did not transduce oncogenic signals. Our results give a clue to account for an underlying cause of HBx-mediated hepatocarcinogenesis. It appears that Ser31 phosphorylation of HBx by Akt plays an important role. The current study provides an example of association of HBV genome variations with risks of HCC and chronic hepatitis.
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: wplee@vghtpe.gov.tw.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Keng-Hsin
authors.initials: KH
authors.lastname: Lan
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan; Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D041681:NIH 3T3 Cells; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D020033:Protein Isoforms; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; HBx; Hepatocellular carcinoma; Phosphorylation