The overexpression of proliferating cell nuclear antigen in biliary cirrhosis in the rat and its relationship with epidermal growth factor receptor

Abstract

Chronic bile duct obstruction in the rat leads to biliary cirrhosis but maintained hepatocellular mass. We have previously demonstrated translocation of epidermal growth factor receptor to nuclei. It remained unclear, however, whether this was due to hepatocyte proliferation and/or altered handling of epidermal growth factor receptor. Therefore, in the present investigation we stereologically estimated expression of proliferating cell nuclear antigen, a marker of the S phase of the cell cycle at 1, 2, 3, 7, 14, 21 and 28 days after bile duct ligation. Proliferating cell nuclear antigen positive hepatocytes averaged 2.1±3.6% in sham-operated control animals. This increased to 20.7±6.4, 26.8±18.7, 31.3±23.9, 42.3±16.6 and 24.7±28.0%, 3, 7, 14, 21 and 28 days after bile duct ligation, respectively ( p<0.005 by ANOVA). This was correlated with the number of epidermal growth factor receptor positive nuclei (r s=0.737) and inversely with the maximal binding capacity of epidermal growth factor to a crude plasma membrane fraction (r s=0.697) reported previously. We conclude that bile duct ligation in the rat induces a significant hepatocellular proliferation as assessed by proliferating cell nuclear antigen expression and that this process could, at least in part, be related to increased nuclear expression of the epidermal growth factor receptor.