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Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver

Vitobello, Antonio and Pouche, Lucie and Romer, Michael and Glogovac, Milica and MacLeod, Kenneth and Ellinger-Ziegelbauer, Heidrun and Westphal, Magdalena and Dubost, Valerie and Stiehl, Daniel Philipp and Dumotier, Berengere and Fekete, Alexander and Moulin, Pierre and Zell, Andreas and Schwarz, Michael and Moreno, Rita and Huang, Jeffrey and Elcombe, Cliff and Henderson, Colin and Wolf, Roland and Moggs, Jonathan and Terranova, Remi (2017) Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver. Toxicological sciences, 158 (2). pp. 367-378. ISSN 1096-0929; 1096-6080

Abstract

Predicting the impact of human exposure to chemicals such as pharmaceuticals and
agrochemicals requires the development of reliable and predictive biomarkers
suitable for the detection of early events potentially leading to adverse outcomes. In
particular, drug-induced non-genotoxic carcinogenesis (NGC) during preclinical
development of novel therapeutics intended for chronic administration in humans is a
major challenge for drug safety.
We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT
signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted
gene cluster non-coding RNAs (ncRNAs) in the liver of mice treated with tumorpromoting
doses of phenobarbital (PB). Here, to explore the sensitivity and the
specificity of this candidate liver tumor promotion ncRNAs signature we compared
phenotypic, transcriptional and proteomic data from wild-type, CAR/PXR double
knock-out and CAR/PXR double humanized animals treated with tumor-promoting
doses of PB or chlordane, both well-established CAR activators. We further
investigated selected transcriptional profiles from mouse liver samples exposed to
seven NGC compounds working through different mode of actions, overall
suggesting CAR-activation specificity of the Dlk1-Dio3 long ncRNAs activation. We
propose that Dlk1-Dio3 long ncRNAs up-regulation is an early CAR-activation
dependent transcriptional signature during xenobiotic-induced mouse liver tumor
promotion. This signature may further contribute mode of action-based ‘weight of
evidence’ cancer risk assessment for xenobiotic-induced rodent liver tumors.

Item Type: Article
Date Deposited: 17 Aug 2017 00:45
Last Modified: 17 Aug 2017 00:45
URI: https://oak.novartis.com/id/eprint/30294

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