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Profound changes in miRNA expression during cancer initiation by aflatoxin B 1 and their abrogation by the chemopreventive triterpenoid CDDO‐Im
Author(s) -
Livingstone Merricka C.,
Johnson Natalie M.,
Roebuck Bill D.,
Kensler Thomas W.,
Groopman John D.
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22635
Subject(s) - aflatoxin , microrna , downregulation and upregulation , biology , carcinogenesis , carcinogen , epigenetics , cancer research , cancer , medicine , genetics , gene , microbiology and biotechnology
Aflatoxin B 1 (AFB 1 ) 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 AFB 1 for 4 week. A panel of miRNAs was identified that was upregulated with AFB 1 treatment 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 AFB 1 plus 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 AFB 1 dosing 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 AFB 1 upregulated 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.