Functional switch of viral protein HBx on cell apoptosis, transformation, and tumorigenesis in association with oncoprotein Ras

The X protein (HBx) of hepatitis B virus (HBV) plays important roles in hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during viral infection. In this study, we demonstrated that co-transfection of mouse embryo fibroblasts (STO) with HBx and activated Ras triggered apoptotic cell death, while HBx or activated Ras individually failed to induce apoptosis. In addition, STO cells were able to form colonies on soft agar after transfected with HBx or Ras, and cells co-transfected with both genes failed to transform. Moreover, nude mice injected with STO cells carrying either HBx or Ras could develop tumor, but tumor growth was inhibited by the injection of both STO cells harboring HBx and carrying Ras. These results suggested that HBx plays a role as a tumor inducer and stimulates neoplastic transformation of normal cells, but shifts its function to the induction of apoptosis in association with Ras.