title: Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion.
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, suggesting 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.
authors.affiliation: Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lempiäinen
authors.forename: Philippe
authors.initials: P
authors.lastname: Couttet
authors.forename: Federico
authors.initials: F
authors.lastname: Bolognani
authors.forename: Arne
authors.initials: A
authors.lastname: Müller
authors.forename: Valérie
authors.initials: V
authors.lastname: Dubost
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Luisier
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio Espinola
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitry
authors.forename: Elif B
authors.initials: EB
authors.lastname: Unterberger
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.forename: Fridolin
authors.initials: F
authors.lastname: Treindl
authors.forename: Ute
authors.initials: U
authors.lastname: Metzger
authors.forename: Clemens
authors.initials: C
authors.lastname: Wrzodek
authors.forename: Florian
authors.initials: F
authors.lastname: Hahne
authors.forename: Tulipan
authors.initials: T
authors.lastname: Zollinger
authors.forename: Sarah
authors.initials: S
authors.lastname: Brasa
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kalteis
authors.forename: Magali
authors.initials: M
authors.lastname: Marcellin
authors.forename: Fanny
authors.initials: F
authors.lastname: Giudicelli
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Laurent
authors.initials: L
authors.lastname: Morawiec
authors.forename: Natasa
authors.initials: N
authors.lastname: Zamurovic
authors.forename: Ulrich
authors.initials: U
authors.lastname: Längle
authors.forename: Nico
authors.initials: N
authors.lastname: Scheer
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.forename: Jay
authors.initials: J
authors.lastname: Goodman
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marlowe
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.forename: David J
authors.initials: DJ
authors.lastname: Heard
authors.forename: Olivier
authors.initials: O
authors.lastname: Grenet
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.forename: Markus F
authors.initials: MF
authors.lastname: Templin
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.forename: Roland C
authors.initials: RC
authors.lastname: Wolf
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Elcombe
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.forename: Rémi
authors.initials: R
authors.lastname: Terranova
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002135:Calcium-Binding Proteins; D000090702:Constitutive Androstane Receptor; D005260:Female; D018392:Genomic Imprinting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D005810:Multigene Family; D016133:Polymerase Chain Reaction; D022661:RNA, Untranslated / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D000090702:Constitutive Androstane Receptor; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D022661:RNA, Untranslated; D018160:Receptors, Cytoplasmic and Nuclear; D051176:beta Catenin; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase