Abstract
The cyclin-dependent kinase inhibitor p21wafl/cipl plays major role in regulation of the cell cycle arrest following DNA damage in a p53-dependent and -independent manner. To elucidate the roles of p21wafl/cipl in selective growth of preneoplastic lesions during chemical hepatocarcinogenesis, p21wafl/cipl expression was examined in the livers of rats fed a 0.02% 2-acetylaminofluorene (2-AAF)-containing diet for 4 weeks or subjected to the protocol of Solt and Farber consisting of a single dose of diethylnitrosamine (DEN) followed 2 weeks later by 2-AAF feeding with two-thirds hepatectomy. By feeding of 2-AAF having a strong mitoinhibitory effect, p21wafl/cipl expression was significantly induced in rat hepatocytes. The proliferating cell nuclear antigen (PCNA) labeling index of hepatocytes was consistently and significantly decreased by 2-AAF feeding. Immunohistochemically, both p21wafl/cipl and p53 were detected in the livers of 2-AAF-fed rats more intensely than in those of control rats. In the livers of rats subjected to the protocol of Solt and Farber, most enzyme-altered foci (EAF) were immunohistochemically negative for p21wafl/cipl, while hepatocytes surrounding the foci were positive. These results clearly show that 2-AAF acts on hepatocytes as a mitoinhibitor by inducing p21wafl/cipl expression, presumably in a p53-dependent manner. Furthermore, the marked difference in p21wafl/cipl expression between non-neoplastic and preneoplastic hepatocytes led to selective growth of preneoplastic lesions during 2-AFF feeding using the protocol of Solt and Farber.
