title: 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.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079, USA. Electronic address: igor.pogribny@fda.hhs.gov.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic; D005663:Furans / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000091102:YAP-Signaling Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D005663:Furans; C574979:MIRN375 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; C039281:furan
keywords: Epigenetic; Furan; Liver cancer; miR-375; miRNAs