Abstract 176: A characteristic set of microRNAs are deregulated in pre-neoplastic liver exposed to chemical carcinogens

Abstract

Abstract This study aimed to identify microRNAs (miRNAs) that were deregulated in pre-neoplastic liver exposed to chemical hepatocarcinogens. Expressions of miRNAs are dysregulated in liver diseases, including hepatocellular carcinomas (HCC). However, the hepatic miRNA profiles at the early stages of liver carcinogenesis, which may be important in cancer initiation and progression, have not so far been thoroughly examined. Male rats were dietary exposed to the maximum tolerated dose of eight compounds, six carcinogens and two non-carcinogens, for a period of 90 days. The selected carcinogens were a diverse group including a genotoxic carcinogen, one carcinogen with a cytotoxic mode of action, a PPARa agonist, a CAR activator, and two chemicals with unknown carcinogenic mechanisms. The non carcinogens were one CAR activator and a chemical with no liver effects. MiRNA microarrays were then used to profile the animals’ liver It was found that at 90 days all tested carcinogens resulted in altered expression of liver miRNAs. It is predicted that some miRNAs altered by a given carcinogen will be chemical-specific and irrelevant to the process of carcinogenesis. Conversely, miRNAs that were deregulated by several carcinogens are more likely to be involved in liver carcinogenesis. A set of ten miRNAs that were deregulated by two or more of the tested carcinogens were identified. These included the miR-200a/200b/429 cluster (induced by five carcinogens), miR-34a (induced by four carcinogens), and the miR-182/96 cluster (induced by four carcinogens). The biggest induction of the miR-200a/200b/429 and miR-182/96 clusters was observed in the livers of animals treated with the CAR activator phenobarbital (PB). To uncover the temporal and dose pattern of the deregulation of these clusters their hepatic expression was assessed in animals treated with one carcinogenic and two non-carcinogenic doses of PB for 1,3,7, and 14 days. A progressive pattern of deregulation was found, with both clusters showing the greatest induction at 90 days, a smaller induction at 14 days, and little or no deregulation at earlier timepoints. Moreover, it was found that induction of the miR-200a/200b/429 and miR-182/96 clusters was specific to the carcinogenic dose of PB. Therefore, the effect of PB on these clusters is both time and dose dependent. Induction of miR-200b was confirmed by qPCR and immunoblotting of its predicted target proteins zeb1 and zeb2. In conclusion, the diverse chemical carcinogens tested here result in the deregulation of a characteristic set of miRNAs in pre-neoplastic liver. These characteristic set did not include a number of miRNAs that have previously been reported to be deregulated in later stages of HCC development (e.g. miR-122, miR-21, miR-221 and let-7). It is possible that the miRNAs identified here are involved in the earliest stages of chemical hepatocarcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 176. doi:10.1158/1538-7445.AM2011-176