Dysregulation of hepatocyte cell cycle and cell viability by hepatitis B virus.

Abstract

Dysregulation of the cell cycle is frequently associated with tumor development. Hepatitis B virus (HBV) is associated with a significant risk of developing hepatocellular carcinoma but the effects of HBV on cell cycle regulation are not completely understood.We have used a recombinant adeno-HBV model system to investigate the effect of infection with HBV and the replication defective lamivudine resistant mutant rtM204I mutant on hepatocyte cell cycle and cell viability.Huh7 cells synchronised at the G1/S phase of the cell cycle were arrested at the G2/M following infection with rAdHBV-wt and rAdHBV-M204I. This was accompanied by increased levels of p21(cip1), p-cdc2, cyclins D, A and B. Cell viability was reduced and cleaved caspase 3 levels were increased in HBV- and rtM204I-infected cells. rAdHBV-M204I-infected Huh7 cells also demonstrated significant up-regulation of phospho-ERK, phospho-Akt, p53 and phospho-Mdm2 compared to mock-infected cells. These changes were comparable to those following infection of Huh7 cells with rAdHBV-wt.Our results suggest that HBV, regardless of phenotype, produces cell cycle arrest and reduced hepatocyte viability. Perturbations in these cellular processes are likely to underlie HBV-associated liver oncogenic transformation and may help explain the ongoing risk of developing hepatocellular carcinoma in individuals in whom the lamivudine resistant rtM204I mutant emerges.