title: Ha-ras and β-catenin oncoproteins orchestrate metabolic programs in mouse liver tumors.
abstract: The process of hepatocarcinogenesis in the diethylnitrosamine (DEN) initiation/phenobarbital (PB) promotion mouse model involves the selective clonal outgrowth of cells harboring oncogene mutations in Ctnnb1, while spontaneous or DEN-only-induced tumors are often Ha-ras- or B-raf-mutated. The molecular mechanisms and pathways underlying these different tumor sub-types are not well characterized. Their identification may help identify markers for xenobiotic promoted versus spontaneously occurring liver tumors. Here, we have characterized mouse liver tumors harboring either Ctnnb1 or Ha-ras mutations via integrated molecular profiling at the transcriptional, translational and post-translational levels. In addition, metabolites of the intermediary metabolism were quantified by high resolution (1)H magic angle nuclear magnetic resonance. We have identified tumor genotype-specific differences in mRNA and miRNA expression, protein levels, post-translational modifications, and metabolite levels that facilitate the molecular and biochemical stratification of tumor phenotypes. Bioinformatic integration of these data at the pathway level led to novel insights into tumor genotype-specific aberrant cell signaling and in particular to a better understanding of alterations in pathways of the cell intermediary metabolism, which are driven by the constitutive activation of the β-Catenin and Ha-ras oncoproteins in tumors of the two genotypes.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology Department of Toxicology, Eberhard Karls University of Tübingen, Tübingen, 72074, Germany.
authors.forename: Elif B
authors.initials: EB
authors.lastname: Unterberger
authors.forename: Johannes
authors.initials: J
authors.lastname: Eichner
authors.forename: Clemens
authors.initials: C
authors.lastname: Wrzodek
authors.forename: Harri
authors.initials: H
authors.lastname: Lempiäinen
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Luisier
authors.forename: Rémi
authors.initials: R
authors.lastname: Terranova
authors.forename: Ute
authors.initials: U
authors.lastname: Metzger
authors.forename: Simon
authors.initials: S
authors.lastname: Plummer
authors.forename: Thomas
authors.initials: T
authors.lastname: Knorpp
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moggs
authors.forename: Markus F
authors.initials: MF
authors.lastname: Templin
authors.forename: Valerie
authors.initials: V
authors.lastname: Honndorf
authors.forename: Martial
authors.initials: M
authors.lastname: Piotto
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D020869:Gene Expression Profiling; D011905:Genes, ras / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger; D051176:beta Catenin
keywords: Ha-ras; microarray; mouse hepatoma; tumor metabolism; β-Catenin