Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of β-catenin

Intrahepatic expression of hepatitis B x antigen (HBxAg) is associated with the development of hepatocellular carcinoma (HCC), perhaps through trans-activation of selected cellular genes. When this was examined by PowerBlot analysis, upregulated levels of β-catenin and several known β-catenin effectors were observed in HBxAg-positive compared with HBxAg-negative HepG2 cells. When HBxAg was introduced into Hep3B cells, upregulated expression of wild-type β-catenin was observed. This was also observed in Hep3B cells overexpressing the HBxAg upregulated gene, URG11. Upregulated expression of URG11 and β-catenin correlated with HBxAg trans-activation function. Transient transfection assays with fragments of the β-catenin promoter showed that it was activated by both HBxAg and URG11 and inhibited by URG11-specific small inhibitory RNA, The latter also inhibited the growth of Hep3BX cells in a serum-free medium, which correlated with depressed levels of β-catenin. Activation of β-catenin effector genes was observed in cells stably expressing HBxAg or overexpressing URG11 compared with control cells transfected with the pTOPFLASH reporter plasmid. Extensive costaining between HBxAg, URG11, and β-catenin was observed in infected liver and HCC nodules, suggesting a close relationship in vivo. In conclusion, wild-type β-catenin is activated by HBxAg, in part, through the upregulated expression of the HBxAg effector URG11. URG11 stimulates the β-catenin promoter and hepatocellular growth and survival. These observations also suggest that URG11 may be a regulatory element in the β-catenin signaling pathway and may be a target for chemoprevention of HCC. Copyright © 2006 by the American Association for the Study of Liver Diseases.