Premature cell cycle entry induced by hepatitis B virus regulatory HBx protein during compensatory liver regeneration

Cancer Res. 2008 Dec 15;68(24):10341-8. doi: 10.1158/0008-5472.CAN-08-2695.


The cycles of cell death and compensatory regeneration that occur during chronic hepatitis B virus (HBV) infection are central to viral pathogenesis and are a risk factor for the development of liver cancer. The HBV genome encodes one regulatory protein, HBx, which is required for virus replication, although its precise role in replication and pathogenesis is unclear. Because HBx can induce the G(0)-G(1) transition in cultured cells, the purpose of this study was to examine the effect of HBx during liver regeneration. Transgenic mice expressing HBx (ATX) and their wild-type (WT) littermates were used in the partial hepatectomy (PH) model for compensatory regeneration. Liver tissues collected from ATX and WT mice at varying sacrifice time points after PH were examined for markers of cell cycle progression. When compared with WT liver tissues, ATX livers had evidence of premature cell cycle entry as assessed by several variables (BrdUrd incorporation, proliferating cell nuclear antigen and mitotic indices, and reduced steady-state p21 protein levels). However, HBx did not affect apoptosis, glycogen storage, or PH-induced steatosis. Together, these results show that HBx expression can induce cell cycle progression within the regenerating liver. Our data are consistent with a model in which HBx expression contributes to liver disease and cancer formation by affecting early steps in liver regeneration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cell Division / physiology
  • DNA / biosynthesis
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / pathology
  • Hepatocytes / cytology
  • Hepatocytes / physiology
  • Liver Regeneration / physiology*
  • Mice
  • Mice, Transgenic
  • Multienzyme Complexes / genetics
  • Phosphodiesterase I / genetics
  • Phosphoric Diester Hydrolases
  • Pyrophosphatases / genetics
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins / biosynthesis
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / physiology*


  • Multienzyme Complexes
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • DNA
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Pyrophosphatases