Profound changes in miRNA expression during cancer initiation by aflatoxin B1 and their abrogation by the chemopreventive triterpenoid CDDO-Im

Merricka C. Livingstone, Natalie M. Johnson, Bill D. Roebuck, Thomas W. Kensler, John D. Groopman

Research output: Contribution to journalArticlepeer-review

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 AFB1 for 4 week. A panel of miRNAs was identified that was upregulated with AFB1 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 AFB1 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 AFB1 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 AFB1 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.

Original languageEnglish (US)
Pages (from-to)2382-2390
Number of pages9
JournalMolecular Carcinogenesis
Volume56
Issue number11
DOIs
StatePublished - Nov 2017

Keywords

  • CDDO-Im
  • RNA sequencing
  • aflatoxin B
  • hepatocellular carcinoma
  • miRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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