Journal
TOXICOLOGICAL SCIENCES
Volume 158, Issue 2, Pages 367-378Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfx104
Keywords
Dlk1-Dio3 cluster; noncoding RNAs; constitutive androstane receptor (CAR); nongenotoxic carcinogenesis (NGC); cancer risk assessment; phenobarbital; chlordane
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Funding
- Innovative Medicine Initiative Joint Undertaking (IMI JU) [115001]
- Cancer Research UK program [C4639/A10822]
- Novartis Institutes for Biomedical Research
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Derisking xenobiotic-induced nongenotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster noncoding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional, and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced nongenotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.
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