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

  • 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 β-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 β-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.

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Author:Harri Lempiäinen, Philippe Couttet, Federico Bolognani, Arne Müller, Valérie Dubost, Raphaëlle 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 Braeuning, Laurent Morawiec, Natasa Zamurovic, Ulrich Längle, Nico ScheerORCiD, Dirk Schübeler, Jay Goodman, Salah-Dine Chibout, Jennifer Marlowe, Dietlinde Theil, David J. Heard, Olivier Grenet, Andreas Zell, Markus F. Templin, Richard R. Meehan, Roland C. Wolf, Clifford R. Elcombe, Michael Schwarz, Pierre Moulin, Rémi Terranova, Jonathan G. Moggs
DOI:https://doi.org/10.1093/toxsci/kfs303
ISSN:1094-2025
Parent Title (English):Toxicological Sciences
Publisher:Oxford University Press
Place of publication:Oxford
Document Type:Article
Language:English
Year of Completion:2012
Date of the Publication (Server):2019/04/11
Volume:131
Issue:2
First Page:375
Last Page:386
Link: https://doi.org/10.1093/toxsci/kfs303
Zugriffsart:weltweit
Institutes:FH Aachen / Fachbereich Chemie und Biotechnologie
collections:Verlag / Oxford University Press