A miRNA signature linked to human environmental risk defined from carcinogen-induced and genetically-driven colon carcinogenesis models
Conference Paper
Overview
Identity
View All
Overview
abstract
Heterocyclic amines (HCAs) produced during high-temperature cooking have been studied extensively in terms of their genetic effects, but recent work has implicated epigenetic mechanisms involving non-coding RNAs. We reported that colon tumors induced in the rat by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) have altered microRNA (miRNA) signatures linked to dysregulated pluripotency factors, such as c-Myc and Krppel-like factor 4 (Klf4). The corresponding miRNAs prioritized from PhIP-induced colon tumors were examined in other target organs from a one-year carcinogenicity bioassay, and compared with miRNAs dysregulated in the Apc-mutant polyposis in rat colon (Pirc) genetic model. Multiple let-7 family members were downregulated in colon, skin, lung, small intestine, and Zymbals gland tumors, and were associated with Myc and Hmga2 upregulation. A PhIP miRNA signature with the profile mir-21high | mir-126low | mir-29low | mir-215low | mir-145low was linked to reduced expression of Klf4 in multiple target organs of the rat, and was predictive of poor prognosis in human pan-cancer and colorectal cancer datasets (https://cancergenome.nih.gov/). Findings from The Cancer Genome Atlas suggested that PhIP signature miRNAs might serve as an arbiter of HCA exposure, defining a subset of human tumors linked to environmental carcinogen exposure. We conclude that future studies should examine the miRNA signatures of other HCAs, and determine their possible predictive value for human risk assessment. This work was supported in part by NIH grants CA090890, CA122959, ES00210, and ES023512, the John S. Dunn Foundation, and a Chancellors Research Initiative. We are most thankful to Robert Hawk for providing a graduate student fellowship in aid of Y-S Chen.
