Lempiaeinen, Harri, Couttet, Philippe, Bolognani, Federico, Mueller, Arne, Dubost, Valerie, Luisier, Raphaelle, Hahne, Florian, Zollinger, Tulipan, Brasa, Sarah, Kalteis, Magdalena, Marcellin, Magali, Morawiec, Laurent, Zamurovic Ribrioux, Natasa, Laengle, Ulrich, Schuebeler, Dirk, Chibout, Salah-Dine, Marlowe, Jennifer, Theil, Diethilde, Heard, David, Grenet, Olivier, Moulin, Pierre, Terranova, Remi, Moggs, Jonathan, Unterberger, Elif, Thomson, John, Treindl, Fridolin, Metzger, Ute, Wrzodek, Clemens, Giudicelli, Fanny Bernadette, Braeuning, Albert, Scheer, Nico, Goodman, Jay, Zell, Andreas, Templin, Markus, Meehan, Richard, Wolf, C. Roland, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/7546