title: Modulation of MAPK pathways and cell cycle by replicating hepatitis B virus: factors contributing to hepatocarcinogenesis.
abstract: OBJECTIVE
  Chronic infection with the hepatitis B virus (HBV) is strongly associated with the development of hepatocellular carcinoma but the mechanism by which this occurs is unknown. Numerous studies have focused on the HBV X protein showing that it activates signal transduction pathways while few have investigated these changes in HBV-replicating hepatocytes.
  
  
  METHODS
  We utilized the recombinant adenovirus system to deliver a replication competent HBV genome into Huh7 and primary marmoset hepatocytes (PMH) to examine the effects of active viral replication on the regulation of Ras-ERK signal transduction and related pathways.
  
  
  RESULTS
  Huh7 cells and PMHs replicating HBV demonstrated significant upregulation in phosphorylated ERK, Akt, c-myc together with increased p53, cyclin B1 and p21(cip1) expression and cell cycle progression to G2 phase in the absence of increased cell proliferation. Phosphorylation of the key cell survival kinase, Akt, was significantly increased, resulting in increased serine phosphorylation of the downstream target, GSK3-beta.
  
  
  CONCLUSIONS
  These results demonstrated simultaneous activation of the MAP Kinase and Akt pathways in HBV-replicating hepatocytes that resulted in dysregulation in the control of cell cycle progression and which help explain the early pathogenic mechanisms that underlie malignant transformation associated with chronic hepatitis B infection.
authors.affiliation: Department of Medicine, CCREID, Royal Melbourne Hospital, University of Melbourne, Post Office, Parkville, Vic. 3050, Australia. rchin@unimelb.edu.au
authors.forename: Ruth
authors.initials: R
authors.lastname: Chin
authors.forename: Linda
authors.initials: L
authors.lastname: Earnest-Silveira
authors.forename: Bernd
authors.initials: B
authors.lastname: Koeberlein
authors.forename: Susanne
authors.initials: S
authors.lastname: Franz
authors.forename: Hanswalter
authors.initials: H
authors.lastname: Zentgraf
authors.forename: Xuebin
authors.initials: X
authors.lastname: Dong
authors.forename: Eric
authors.initials: E
authors.lastname: Gowans
authors.forename: C-Thomas
authors.initials: CT
authors.lastname: Bock
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
mesh_terms: D000818:Animals; D002144:Callithrix; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology / Q000821:virology*; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D016195:G2 Phase; D006515:Hepatitis B virus / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology*; D022781:Hepatocytes / Q000821:virology; D008113:Liver Neoplasms / Q000503:physiopathology / Q000821:virology*; D020935:MAP Kinase Signaling System; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D014779:Virus Replication
chemical_list: D019925:Cyclin A; D019926:Cyclin B; D016271:Proto-Oncogene Proteins c-myc; D051057:Proto-Oncogene Proteins c-akt