title: Profound changes in miRNA expression during cancer initiation by aflatoxin B1and their abrogation by the chemopreventive triterpenoid CDDO-Im.
abstract: Aflatoxin B1(AFB1) is a potent human and animal hepatocarcinogen. To investigate the effects of aflatoxin on miRNA expression during the initiation phase of carcinogenesis, next-generation sequencing was used to analyze liver tissues from F344 rats exposed to 200 μg/kg per day AFB1for 4 week. A panel of miRNAs was identified that was upregulated with AFB1treatment compared to controls: rno-miR-434-3p, rno-miR-411-5p, rno-miR-221-3p, rno-miR-127-3p, rno-miR-205, rno-miR-429, rno-miR-34a-5p, rno-miR-181c-3p, rno-miR-200b-3p, and rno-miR-541-5p. Analysis of rat livers exposed to AFB1plus the chemopreventive triterpenoid CDDO-Im revealed a striking abrogation of this upregulation. These changes were validated by real-time PCR. We also explored the temporal variation in expression of the candidate miRNAs during the 4-week dosing period. Most of the candidate miRNAs were upregulated at week 1 and increased for the duration of AFB1dosing over the 4-week period. Treatment with CDDO-Im ameliorated these effects at all time points. All candidate miRNAs were detectable in serum from aflatoxin treated animals; however, there was no significant difference in expression for 7 of the 11 miRNAs examined. Exposure to AFB1upregulated miR-122-5p (fivefold), 34a-5p (13-fold), and 181c-3p (170-fold) compared with controls. The findings from this study give insight into epigenetic changes induced by aflatoxin taking place during the initial step of carcinogenesis.
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Merricka C
authors.identifier: http://orcid.org/0000-0002-5487-4905
authors.initials: MC
authors.lastname: Livingstone
authors.affiliation: Texas A&M School of Public Health, College Station, Texas.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Johnson
authors.affiliation: Dartmouth College School of Medicine, Hanover, New Hampshire.
authors.forename: Bill D
authors.initials: BD
authors.lastname: Roebuck
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
mesh_terms: D016604:Aflatoxin B1 / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001231:Aspergillus flavus / Q000737:chemistry; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007093:Imidazoles / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011916:Rats, Inbred F344
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007093:Imidazoles; D035683:MicroRNAs; D009828:Oleanolic Acid; D016604:Aflatoxin B1
keywords: CDDO-Im; RNA sequencing; aflatoxin B1; hepatocellular carcinoma; miRNA