Identification of Dlk1-Dio3 Imprinted Gene Cluster Noncoding RNAs as Novel Candidate Biomarkers for Liver Tumor Promotion

Harri Lempiainen, Philippe Couttet, Federico Bolognani, Arne Mueller, Valerie Dubost, Raphaelle Luisier, Alberto Del Rio Espinola, Veronique Vitry, Elif B. Unterberger, John P. Thomson, Fridolin Treindl, Ute Metzger, Clemens Wrzodek, Florian Hahne, Tulipan Zollinger, Sarah Brasa, Magdalena Kalteis, Magali Marcellin, Fanny Giudicelli, Albert BraeuningLaurent Morawiec, Natasa Zamurovic, Ulrich Laengle, Nico Scheer, Dirk Schuebeler, Jay Goodman, Salah-Dine Chibout, Jennifer Marlowe, Diethilde Theil, David J. Heard, Olivier Grenet, Andreas Zell, Markus F. Templin, Richard R. Meehan, Roland C. Wolf, Clifford R. Elcombe, Michael Schwarz, Pierre Moulin, Remi Terranova, Jonathan G. Moggs

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular events during nongenotoxic 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 (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs 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. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for -catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and -catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.

Original languageEnglish
Pages (from-to)375-386
Number of pages12
JournalToxicological Sciences
Volume131
Issue number2
DOIs
Publication statusPublished - Feb 2013

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