Metabolic programs orchestrated by the activated Ha-ras and -catenin oncoproteins in mouse liver tumors [mRNA]

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 Ha-ras, B-raf, or Ctnnb1. Here, we have characterized mouse liver tumors harboring either Ctnnb1 or Ha-ras mutations via integrated molecular profiling at the transcriptional and translational and post-translational levels. In addition, metabolites of the intermediary metabolism were quantified by high resultion 1H magic angle nuclear magnetic resonance (HR-MAS NMR). We have identified tumor characteristic genotype-specific differences in mRNA and miRNA expression, protein levels, and post-translational modifications and in 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 -Catenin and Ha-ras oncoproteins in tumors of the two genotypes.

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Unterberger EB, Eichner J, Wrzodek C, Lempiäinen H, Luisier R, Terranova R, Metzger U, Plummer S, Knorpp T, Braeuning A, Moggs J, Templin MF, Honndorf V, Piotto M, Zell A, Schwarz M