CELL-PROLIFERATION AND ADVANCEMENT OF HEPATOCARCINOGENESIS IN THE RAT ARE ASSOCIATED WITH A DECREASE IN CONNEXIN-32 EXPRESSION

The expression of connexin 32 (Cx32), a major liver gap junction protein, after partial hepatectomy (PH) and during development and progression of hepatocarcinogenesis was studied in the rat, Cx32 was quantitatively analyzed by counting immunohistochemically demonstrated protein spots on the membranes of hepatocytes. Livers were sequentially examined after PH to assess the correlation with cell proliferation. For the analysis of different stages in carcinogenesis, Cx32 was assayed in N-ethyl-N-hydroxyethylnitrosamine-induced enzyme altered foci (EAF), hyperplastic nodules (HN), hepatocellular carcinomas (HCC), pulmonary metastatic HCC and transplanted HCC in relation to their degree of altered enzyme expression, Cx32 showed: (i) a rapid decrease after PH to its lowest levels during and 12 h after the S phase of cell proliferation when 5-bromo-2'-deoxyuridine (BrdU) labeling indices were examined; (ii) a progressive decrease from early preneoplasia EAF to HN and HCC, values for pulmonary metastatic and transplanted HCC being 0; (iii) clearly inverse correlations with increased BrdU index and degree of altered enzyme expression in HN, indicating that these, with the lowest Cx32 count, are closest to HCC. Therefore, the observed decrease appears linked to cell proliferation and progression of hepatocarcinogenesis, providing a reflection of cellular independence and growth advantage.