We have 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 Srebp1was 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.Previously, we showed that activation of the beta-catenin/Wnt pathway is a dominant event during c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs displayed nuclear accumulation of beta-catenin in the absence of beta-catenin mutations, suggesting that alterations in other members of the Wnt pathway might be responsible for nuclear localization of beta-catenin. Here, we investigated the mechanisms responsible for nuclear translocation of wild-type beta-catenin and addressed the potential contribution of the Wnt pathway in c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs exhibited multiple abnormalities in the Wnt pathway regardless of the presence of beta-catenin mutations. The observed abnormalities included overexpression of Wnt-1, Frizzled 1 and 2 receptors, Dishevelled-1, downregulation of Secreted frizzled-related protein-1, GSK-3b inactivation, microsatellite instability at the Axin locus as well as induction of beta-catenin target genes, such as glutamine synthetase, glutamate transporter-1, and Wisp-1. HCCs with beta-catenin activation displayed significantly higher proliferation rate and larger tumor size when compared with beta-catenin negative tumors.We conclude that the data demonstrate multiple abnormalities in the members of the Wnt pathway lead to nuclear accumulation of beta-catenin and suggest that activation of Wnt pathway provides proliferative advantages in c-Myc/E2F1-driven hepatocarcinogenesis.
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