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Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion

Lempiaeinen, Harri and Couttet, Philippe and Bolognani, Federico and Mueller, Arne and Dubost, Valerie and Luisier, Raphaelle and Hahne, Florian and Zollinger, Tulipan and Brasa, Sarah and Kalteis, Magdalena and Marcellin, Magali and Morawiec, Laurent and Zamurovic Ribrioux, Natasa and Laengle, Ulrich and Schuebeler, Dirk and Chibout, Salah-Dine and Marlowe, Jennifer and Theil, Diethilde and Heard, David and Grenet, Olivier and Moulin, Pierre and Terranova, Remi and Moggs, Jonathan and Unterberger, Elif and Thomson, John and Treindl, Fridolin and Metzger, Ute and Wrzodek, Clemens and Giudicelli, Fanny Bernadette and Braeuning, Albert and Scheer, Nico and Goodman, Jay and Zell, Andreas and Templin, Markus and Meehan, Richard and Wolf, C. Roland and Elcombe, Clifford and Schwarz, Michael (2012) Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion. Toxicological Sciences. ISSN 1096-6080

Abstract

The molecular events during non-genotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital-mediated liver tumor promotion in vivo. Molecular profiling (mRNA, miRNA, DNA methylation & proteins) of mouse liver during 13 weeks of phenobarbital treatment revealed progressive increases in hepatic expression of long non-coding RNAs and microRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. Phenobarbital-induction of the Dlk1-Dio3 cluster non-coding RNA Meg3 was localised to glutamine synthetase positive hypertrophic perivenous hepatocytes suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 non-coding RNAs. The carcinogenic relevance of Dlk1-Dio3 locus non-coding RNA induction was further supported by in vivo genetic dependence on Constitutive Androstane Receptor (CAR) and β-catenin pathways. Our data identify Dlk1-Dio3 non-coding RNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7546

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