title: Genotype-phenotype relationships in hepatocellular tumors from mice and man.
abstract: Experimentally induced liver tumors in mice harbor activating mutations in either Catnb (beta-catenin) or Ha-ras, according to the carcinogenic treatment. We have now investigated by microarray analysis the gene expression profiles in tumors of the two genotypes. In total, 364 genes or expressed sequences with aberrant expression relative to normal liver were identified, but only 30 of these demonstrated unidirectional changes in both tumor types. Several functional clusters were identified that involve changes in amino acid utilization and ammonia disposition in Catnb-mutated tumors as opposed to alterations in lipid and cholesterol metabolism in Ha-ras-mutated tumors. Moreover, several genes coding for inhibitory molecules within the Wnt-signaling pathway were upregulated in Catnb-mutated tumors, suggesting induction of a negative feedback loop, whereas Ha-ras-mutated tumors showed alterations in the expression of several genes functional in monomeric G-protein signaling. We conclude that mouse hepatoma cells adopt different evolutionary strategies that allow for their selective outgrowth under variable environmental conditions. Human hepatocellular cancers (HCC) lack RAS mutations but are frequently mutated in CTNNB1, the human Catnb ortholog. The set of genes aberrantly expressed in Catnb-mutated mouse tumors was used to screen, by expression profiling, for dysregulation of orthologous genes within a panel of 25 HCCs, of which 10 were CTNNB1-mutated. HCCs with activated beta-catenin displayed a gene expression profile that was similar to Catnb-mutated mouse tumors but distinct from the other human HCCs. In conclusion, expression fingerprints may be used for diagnostic purposes and potential new therapeutic intervention strategies. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index/html).
authors.affiliation: Institut für Pharmakologie und Toxikologie, Abteilung Toxikologie, Universität Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Stahl
authors.forename: Carina
authors.initials: C
authors.lastname: Ittrich
authors.forename: Philip
authors.initials: P
authors.lastname: Marx-Stoelting
authors.forename: Christoph
authors.initials: C
authors.lastname: Köhle
authors.forename: Ozge
authors.initials: O
authors.lastname: Altug-Teber
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Jürgen
authors.initials: J
authors.lastname: Jobst
authors.forename: Stephan
authors.initials: S
authors.lastname: Kaiser
authors.forename: Albrecht
authors.initials: A
authors.lastname: Buchmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D011905:Genes, ras; D005838:Genotype; D005974:Glutamate-Ammonia Ligase / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase