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.
@article{Harri2012,
author = {Harri Lempi\"ainen and Philippe Couttet and Federico Bolognani and
Arne M\"uller and Val\'{e}rie Dubost and Rapha\"elle Luisier and
Espinola Alberto {Del Rio} and Veronique Vitry and Elif B Unterberger
and John P Thomson and Fridolin Treindl and Ute Metzger and Clemens
Wrzodek and Florian Hahne and Tulipan Zollinger and Sarah Brasa and
Magdalena Kalteis and Magali Marcellin and Fanny Giudicelli and Albert
Braeuning and Laurent Morawiec and Natasa Zamurovic and Ulrich L\"angle
and Nico Scheer and Dirk Sch\"ubeler and Jay Goodman and Salah-Dine
Chibout and Jennifer Marlowe and Diethilde Theil and David J Heard
and Olivier Grenet and Andreas Zell and Markus F Templin and Richard
R Meehan and {C. Roland} Wolf and Clifford R Elcombe and Michael
Schwarz and Pierre Moulin and R\'{e}mi Terranova and Jonathan G Moggs},
title = {{Identification of \emph{Dlk1}-\emph{Dio3} imprinted gene cluster
non-coding RNAs as novel candidate biomarkers for liver tumor promotion}.},
journal = {Toxicological Sciences},
year = {2012},
volume = {131},
pages = {375--386},
number = {2},
month = oct,
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
$\beta$-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 $\beta$-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.},
doi = {10.1093/toxsci/kfs303},
eprint = {http://toxsci.oxfordjournals.org/content/131/2/375.full.pdf+html},
institution = {Discovery and Investigative Safety, Preclinical Safety, Novartis
Institutes for Biomedical Research, CH-4057 Basel, Switzerland.},
keywords = {Non-genotoxic carcinogenesis, Phenobarbital, biomarker, non-coding
RNAs, Dlk1-Dio3 Imprinted cluster, epigenetics},
language = {eng},
pdf = {http://toxsci.oxfordjournals.org/content/131/2/375.full.pdf},
pii = {kfs303},
pmid = {23091169},
url = {http://toxsci.oxfordjournals.org/content/131/2/375.abstract}
}