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Published on: October 23, 2018
Xenobiotic CAR Activators Induce Dlk1-Dio3 Locus Noncoding RNA Expression in Mouse Liver
Lucie Pouché1, Antonio Vitobello1, Michael Römer2
1Preclinical Safety, Translational Medicine, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland.
Abstract:
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.
Insights
Identifying novel biomarkers for chemical-induced cancer is crucial for drug safety. This study shows that Dlk1-Dio3 noncoding RNAs can serve as early indicators of nongenotoxic carcinogenesis, particularly for Constitutive Androstane Receptor (CAR) activator-induced liver cancer.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- Nongenotoxic carcinogenesis (NGC) poses challenges in chemical and drug safety assessment.
- Mechanism-based biomarkers are needed to improve cancer hazard identification.
- Previously, Constitutive Androstane Receptor (CAR) and WNT signaling influenced Dlk1-Dio3 noncoding RNA (ncRNA) upregulation in mice treated with phenobarbital (PB).
Purpose of the Study:
- To investigate the role of the Dlk1-Dio3 imprinted gene cluster ncRNAs as potential biomarkers for NGC.
- To determine if Dlk1-Dio3 ncRNA upregulation is dependent on CAR/PXR activation by different chemicals.
- To assess the specificity of Dlk1-Dio3 ncRNAs as biomarkers for various NGC modes of action.
Main Methods:
- Comparison of phenotypic, transcriptional, and proteomic data in wild-type, CAR/PXR double knock-out, and CAR/PXR double humanized mice.
- Treatment of mice with phenobarbital (PB) or chlordane, known CAR activators.
- Analysis of Dlk1-Dio3 locus ncRNA expression in response to different compounds with distinct NGC mechanisms.
Main Results:
- Hepatic Dlk1-Dio3 locus long ncRNAs were upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators (PB and chlordane).
- The upregulation of Dlk1-Dio3 ncRNAs was observed in response to CAR activators.
- Exploration of specificity indicated that Dlk1-Dio3 ncRNAs are potential biomarkers for CAR activator-induced NGC.
Conclusions:
- Up-regulation of Dlk1-Dio3 cluster ncRNAs serves as an early biomarker for CAR activator-induced nongenotoxic hepatocarcinogenesis.
- These ncRNAs can contribute to mechanism-based assessments of carcinogenicity risk for chemicals and therapeutics.
- This finding enhances the identification of potential liver cancer hazards during safety evaluations.
