The anticancer effects of 5-aza-2'deoxycytidine as a DNA demethylation agent on NNK-induced rat hepatocellular carcimonas

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Hepatocellular tumors were induced in male Fischer 344 rats by treatment with the 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) three times a week (50 mg/kg intraperitoneally injection) for 20 weeks. Based on histopathological analysis, these tumors were diagnosed as carcinomas (12 nodules/total 28 nodules) and adenomas (16 nodules/total 28 nodules).RNA and DNA were isolated from these hepatocellular carcinomas. To determine gene expression changes associated with NNK exposure to genotoxic carcinogens, these RNA were subjected to microarray analysis. A number of genes were down-regulated by NNK exposure compared with controls. The methylation status of these down-regulated genes were determined by methylation-specific PCR (MSP). Overall, the promoter region hypermethylation of the p16 and E-cadherin genes were detected. The protein expression levels of p16 and E-cadherin were examined by immunohistochemical staining. The expression levels of these proteins were also down-regulated.The anticancer effects of 5-aza-2'deoxycytidine once a week (1 mg/kg intraperitoneally injection) as a DNA demethylation agent on NNK-induced rat hepatocellular carcimonas were investigated. Our results suggested that 5-aza-2'deoxycytidine did not influence on the potency of hepatocarcinogenesis induced by NNK, the progression of hepatocellular carcinomas and the methylation status of p16 and E-cadherin genes methylated with NNK treatment.