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.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010036-11
Application #
7338280
Study Section
(LEC)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Matter, Matthias S; Marquardt, Jens U; Andersen, Jesper B et al. (2016) Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology 63:1888-99
Coulouarn, Cedric; Factor, Valentina M; Thorgeirsson, Snorri S (2008) Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47:2059-67
van Hagen, J M; van der Geest, J N; van der Giessen, R S et al. (2007) Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol Dis 26:112-24
Martin, Juliette; Magnino, Fabrice; Schmidt, Karin et al. (2006) Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma. Gastroenterology 130:2179-88
Cavin, Lakita G; Wang, Fang; Factor, Valentina M et al. (2005) Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappaB in murine hepatocellular carcinomas. Mol Cancer Res 3:403-12
Durkin, Marian E; Avner, Miriam R; Huh, Chang-Goo et al. (2005) DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS Lett 579:1191-6
Calvisi, Diego F; Thorgeirsson, Snorri S (2005) Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer. Toxicol Pathol 33:181-4
Karlsson, Goran; Liu, Yingchun; Larsson, Jonas et al. (2005) Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling. Physiol Genomics 21:396-403
Meyer, Kirstin; Lee, Ju-Seog; Dyck, Patricia A et al. (2003) Molecular profiling of hepatocellular carcinomas developing spontaneously in acyl-CoA oxidase deficient mice: comparison with liver tumors induced in wild-type mice by a peroxisome proliferator and a genotoxic carcinogen. Carcinogenesis 24:975-84
Arsura, Marcello; Panta, Ganesh R; Bilyeu, Jennifer D et al. (2003) Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22:412-25

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