Differences in Expression Patterns of Cell Cycle Regulators after Cessation of Genotoxic and Non-genotoxic Carcinogen Treatment in the Rat Forestomach

Abstract

We have already shown that forestomach lesions induced by 24 weeks administration of genotoxic carcinogens, 8-nitroquinoline (8-NQ), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methylnitrosourethane (MNUR), do not regress within 24 weeks of cessation of the chemical exposure. In contrast, simple or papillary hyperplasias induced by 24 weeks administration of non-genotoxic carcinogens, butylated hydroxyanisole (BHA), caffeic acid (CA), sesamol or 4-methoxyphenol (4-MP), largely disappear. In the present study, to examine the mechanisms of the reversibility of proliferative forestomach lesions, representative non-genotoxic carcinogens, BHA, CA or 4-MP, and one genotoxic carcinogen, MNUR, were given to male F344 rats for 24 weeks, then their forestomachs were sequentially analyzed after withdrawal of the chemical insult. MNUR-induced proliferative lesions such as hyperplasias, papillomas and squamous cell carcinomas did not regress and the expression level of cell cycle regulators, cyclin D1 and p27 were not altered after cessation of the chemical insult. On the other hand, BHA-, CA- or 4-MP-induced hyperplasias clearly regressed, in association with reduction of cyclin D1 expression. During this process, expressions of p27 and cleaved caspase 3 were not altered. These findings suggest that regression of proliferative lesions induced by non-genotoxic rat forestomach carcinogens is controlled partially by a positive cell cycle regulator, cyclin D1, whereas dysregulation of this mechanism is a characteristic of the irreversible lesions induced by a genotoxic carcinogen.