Irreversible down-regulation of miR-375 in the livers of Fischer 344 rats after chronic furan exposure

Abstract

Furan, a rodent liver carcinogen, is a chemical contaminant found in a broad range of cooked foods. Despite a lack of conclusive evidence regarding furan genotoxicity, several reports indicate that furan induces a broad range of non-genotoxic alterations, including aberrant expression microRNAs (miRNAs). In order to clarify the role of miRNA alterations with respect to furan carcinogenicity, we investigated the expression of several cancer-related miRNAs in the livers of Fischer 344 rats treated continuously with furan. The results demonstrate that furan induced marked changes in miRNA expression, characterized by over-expression of hepatic miRNAs, miR-34a, miR-93, miR-200a, miR-200b, and miR-224, and down-regulation of miR-375. Interestingly, a majority of furan-induced miRNA changes diminished after the cessation of the furan treatment. In contrast, the expression of miR-375 steadily decreased in a time-dependent manner following furan treatment. The reduced expression of miR-375 was accompanied by cytosine DNA hypermethylation and increased lysine methylation of histone H3K9 and H3K27 at the MiR-375 gene. The significance of miR-375 inhibition with respect to the pathogenesis of furan-induced liver toxicity and carcinogenicity may be attributed to its role in the up-regulation of Yes-associated protein 1 (YAP1), which is one of the principal events in the liver carcinogenesis. The results of the present study support the hypothesis of the non-genotoxic mode of action of furan and emphasize the importance of epigenetic alterations in the mechanism of furan hepatotoxicity.