Activation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through AP-2 sites.

The HBx protein is known as a transactivator and potential oncogene, and TGF-alpha as a potent mitogen in hepatocellular carcinoma. By assays of serial deletion of the promoter of TGF-alpha gene and the cotransfection of HBx and AP-2 expression vectors, we observed that the HBx significantly activated the promoter activity through AP-2 sites located in the proximal region of the TGF-alpha promoter (-136 to -30). This effect was also observed in the heterologous promoter assay system containing AP-2 sites. The mutation analyses of three AP-2 sites in the promoter revealed that all three AP-2 sites contributed to the activation of the TGF-a gene in the presence of HBx. Accordingly, the mRNA level of TGF-alpha was significantly elevated in the HBx-expressing cell, HepG2-HBx and the HBV-producing cell, HepG2-K8. These results suggest that the HBx protein could increase the mitogenic effect of TGF-alpha by the transactivation of the gene through AP-2 binding sites and consequently, these interactions may accelerate the process of hepatocarcinogenesis.