Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis

Exp Mol Pathol. 2004 Feb;76(1):44-50. doi: 10.1016/j.yexmp.2003.09.001.


The hepatitis B virus X (HBx) protein is thought to be implicated in the development of human hepatocellular carcinoma (HCC), but its exact function remains controversial. To investigate whether the expression of the HBx gene alone can induce HCC on an inbred C57BL/6 strain that displays a lower spontaneous rate of liver cancer, and to determine if HBx transgenic mice are more susceptible to the effects of hepatocarcinogens, C57-TgN (HBx) X transgenic mice were bred with normal C57BL/6 mice strain. The F1 mice (about 50% HBx positive and 50% HBx negative) were treated with a single dose of diethylnitrosamine (DEN) at 7 days of age, or were untreated. Mice were killed at appropriate time points and were analyzed for histological change in the liver. The expression of HBx protein were examined by using immunohistochemical staining. Glycogen storage foci were examined by using periodic acid-Schiff (PAS) staining. In HBx transgenic mice untreated with DEN, HBx expression and glycogen storage foci were always observed in the liver after 8 weeks, but not obvious histological pathologic changes. Histological examination of liver tissue confirmed that DEN-treated HBx mice developed approximately twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Hepatocellular adenomas and carcinomas were also more frequent in DEN-treated HBx-positive than HBx-negative mice. Taken together, our results suggest that HBx gene expression alone is not sufficient for carcinogenesis, but may act as a promoter for malignant transformation.

MeSH terms

  • Adenoma, Liver Cell / chemically induced
  • Adenoma, Liver Cell / metabolism*
  • Adenoma, Liver Cell / pathology
  • Animals
  • Carcinogenicity Tests
  • Carcinogens / toxicity
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Diethylnitrosamine / toxicity
  • Genetic Predisposition to Disease*
  • Liver Glycogen / metabolism
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / metabolism*
  • Liver Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Periodic Acid-Schiff Reaction
  • Precancerous Conditions / chemically induced
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism*


  • Carcinogens
  • Liver Glycogen
  • Trans-Activators
  • hepatitis B virus X protein
  • Diethylnitrosamine