Failure of lamivudine to reverse HBV associated changes in ERK, AKT and cell cycle regulatory proteins

Background: Chronic infection with hepatitis B virus (HBV) is a major factor associated with the development of hepatocellular carcinoma, but the mechanism by which this occurs is unknown. Treatment of chronic hepatitis B with lamivudine results in virological suppression and histological improvement; however, the role of lamivudine in preventing the development of hepatocellular carcinoma is less well defined. We recently reported that replication of HBV in a cell-culture system was associated with the upregulation of pERK, pAkt, pc-Myc, nuclear cyclin B1, p21(cip1) and p53 together with 62 cell cycle arrest. Methods: In order to determine whether lamivudine is able and cell cycle, we infected Huh7 cells with a recombinant adeno-HBV virus in the presence of 0-50 mu M of lamivudine. Signal transduction and cell cycle regulatory proteins were analysed by western immunoblot. Results: Although lamivudine was able to inhibit HBV replication, it failed to reverse the changes on ERK and Akt phosphorylation. Correspondingly, levels of phospho-GSK3 beta and p21(cip1/waf1) were increased, as were cyclin D1, cyclin B1, p53 and pc-Myc. Conclusions: Lamivudine was ineffective in reversing the HBV-induced changes in signal transduction pathways and cell cycle regulatory proteins, indicating that the HBV-infected cells remained primed for oncogenic to reverse the HBV-induced changes on signal transduction transformation despite viral suppression.