title: Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis.
abstract: We applied a genome-wide microarray analysis to three transgenic mouse models of liver cancer in which targeted overexpression of c-Myc, E2f1, and a combination of the two was driven by the albumin promoter. Although gene expression profiles in HCC derived in all three transgenic lines were highly similar, oncogene-specific gene expression signatures were identified at an early dysplastic stage of hepatocarcinogenesis. Overexpression of E2f1 was associated with a strong alteration in lipid metabolism, and Srebp1 was identified as a candidate transcription factor responsible for lipogenic enzyme induction. The molecular signature of c-Myc overexpression included the induction of more than 60 genes involved in the translational machinery that correlated with an increase in liver mass. In contrast, the combined activity of c-Myc and E2f1 specifically enhanced the expression of genes involved in mitochondrial metabolism--particularly the components of the respiratory chain--and correlated with an increased ATP synthesis. Thus, the results suggest that E2f1, c-Myc, and their combination may promote liver tumor development by distinct mechanisms. In conclusion, determination of tissue-specific oncogene expression signatures might be useful to identify conserved expression modules in human cancers.
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cédric
authors.initials: C
authors.lastname: Coulouarn
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gomez-Quiroz
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Pal
authors.initials: P
authors.lastname: Kaposi-Novak
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Conner
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Goldina
authors.forename: Galina E
authors.initials: GE
authors.lastname: Onishchenko
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Factor
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D004260:DNA Repair; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D050356:Lipid Metabolism / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D000255:Adenosine Triphosphate