STRONG, SUSTAINED HEPATOCELLULAR PROLIFERATION PRECEDES HEPATOCARCINOGENESIS IN HEPATITIS-B SURFACE-ANTIGEN TRANSGENIC MICE

Hepatocyte turnover rates were studied in two lineages of transgenic m ice that overproduce the hepatitis B virus (HBV) large envelope protei n and retain filamentous hepatitis B surface antigen (HBsAg) particles in the endoplasmic reticulum, resulting in the formation of ground gl ass hepatocytes, The high producer lineage (50-4) develops a necroinfl ammatory liver disease that progresses to hepatocellular carcinoma (HC C), whereas the low producer Lineage (107-5) displays no histopatholog ic changes other than ground glass hepatocytes. Bromodeoxyuridine (Brd U)-labeling studies of S-phase hepatocytes provide quantitative eviden ce for a strong, sustained proliferative response in the hepatocytes i n lineage 50-4 that occurs after the onset of hepatocellular injury bu t long before the development of Liver cell tumors. In contrast, the l evel of hepatocellular proliferation in lineage 107-5 is the same as n ontransgenic controls, The findings support the concept that sustained hepatocellular proliferation plays an important role in the developme nt of hepatocellular carcinoma (HCC).