Modulation of MAPK pathways and cell cycle by replicating hepatitis B virus: factors contributing to hepatocarcinogenesis.
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.
Chin
Ruth
R
Department of Medicine, CCREID, Royal Melbourne Hospital, University of Melbourne, Post Office, Parkville, Vic. 3050, Australia. rchin@unimelb.edu.au
Earnest-Silveira
Linda
L
Koeberlein
Bernd
B
Franz
Susanne
S
Zentgraf
Hanswalter
H
Dong
Xuebin
X
Gowans
Eric
E
Bock
C-Thomas
CT
Torresi
Joseph
J
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
D019925:Cyclin A; D019926:Cyclin B; D016271:Proto-Oncogene Proteins c-myc; D051057:Proto-Oncogene Proteins c-akt