Increased expression of ErbB‐2 in liver is associated with hepatitis B × antigen and shorter survival in patients with liver cancer

Hepatitis B x antigen, or HBxAg, contributes importantly to the pathogenesis of hepatocellular carcinoma (HCC). Given that HBxAg constitutively activates β-catenin and that up-regulated ErbB2 promotes β-catenin signaling in other tumor types, experiments were designed to ask whether HBxAg was associated with up-regulated expression of ErbB2. When HBxAg positive and negative HepG2 cells were subjected to proteomics analysis, ErbB2 was shown to be upregulated in HepG2X but not control cells. ErbB2 was also strongly up-regulated in hepatitis B infected liver, and weakly in some HCC nodules, where it correlated with HBxAg expression. Among tumor bearing patients, strong ErbB2 staining in the liver was associated with dysplasia, and a shorter survival after tumor diagnosis. This implies that elevated ErbB2 is an early marker of HCC. Treatment of HepG2X cells with ErbB2 specific siRNA not only reduced ErbB2 expression, but also reduced the expression of β-catenin, suggesting that ErbB2 contributed to the stabilization of β-catenin. ErbB2 specific siRNA also partially blocked the ability of HBxAg to promote DNA synthesis and growth of HepG2 cells. These results suggest that ErbB2/β-catenin up-regulation contributes importantly to the mechanism of HBxAg mediated hepatocellular growth.