TY  - JOUR
A1  - Lempiäinen, Harri
A1  - Couttet, Philippe
A1  - Bolognani, Federico
A1  - Müller, Arne
A1  - Dubost, Valérie
A1  - Luisier, Raphaëlle
A1  - Rio-Espinola, Alberto del
A1  - Vitry, Veronique
A1  - Unterberger, Elif B.
A1  - Thomson, John P.
A1  - Treindl, Fridolin
A1  - Metzger, Ute
A1  - Wrzodek, Clemens
A1  - Hahne, Florian
A1  - Zollinger, Tulipan
A1  - Brasa, Sarah
A1  - Kalteis, Magdalena
A1  - Marcellin, Magali
A1  - Giudicelli, Fanny
A1  - Braeuning, Albert
A1  - Morawiec, Laurent
A1  - Zamurovic, Natasa
A1  - Längle, Ulrich
A1  - Scheer, Nico
A1  - Schübeler, Dirk
A1  - Goodman, Jay
A1  - Chibout, Salah-Dine
A1  - Marlowe, Jennifer
A1  - Theil, Dietlinde
A1  - Heard, David J.
A1  - Grenet, Olivier
A1  - Zell, Andreas
A1  - Templin, Markus F.
A1  - Meehan, Richard R.
A1  - Wolf, Roland C.
A1  - Elcombe, Clifford R.
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Rémi
A1  - Moggs, Jonathan G.
T1  - Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion
JF  - Toxicological Sciences
N2  - 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.
Y1  - 2012
U6  - http://dx.doi.org/10.1093/toxsci/kfs303
SN  - 1094-2025
VL  - 131
IS  - 2
SP  - 375
EP  - 386
PB  - Oxford University Press
CY  - Oxford
ER  -