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Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer

Calvisi, Diego Francesco and Conner, Elizabeth A. and Ladu, Sara and Lemmer, Eric R. and Factor, Valentina M. and Thorgeirsson, Snorri S. (2005) Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer. Journal of Hepatology, Vol. 42 (6), p. 842-849. ISSN 0168-8278. Article.

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DOI: 10.1016/j.jhep.2005.01.029

Abstract

Background/Aims. Previously, we showed that activation of the β-catenin/Wnt pathway is a dominant event during c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs displayed nuclear accumulation of β-catenin in the absence of β-catenin mutations, suggesting that alterations in other members of the Wnt pathway might be responsible for nuclear localization of β-catenin. Here, we investigated the mechanisms responsible for nuclear translocation of wild-type β-catenin and addressed the potential contribution of the Wnt pathway in c-Myc/E2F1 hepatocarcinogenesis. Methods. Status of the members of the Wnt pathway was determined through microsatellite and Western blot analysis. Results. Majority of c-Myc/E2F1 HCCs exhibited multiple abnormalities in the Wnt pathway regardless of the presence of β-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-3β inactivation, microsatellite instability at the Axin locus as well as induction of β-catenin target genes, such as glutamine synthetase, glutamate transporter-1, and Wisp-1. HCCs with β-catenin activation displayed significantly higher proliferation rate and larger tumor size when compared with β-catenin negative tumors. Conclusions. The data demonstrate that multiple abnormalities in the members of the Wnt pathway lead to nuclear accumulation of β-catenin and suggest that activation of Wnt pathway provides proliferative advantages in c-Myc/E2F1-driven hepatocarcinogenesis.

Item Type:Article
ID Code:1283
Status:Published
Refereed:Yes
Uncontrolled Keywords:C-Myc, E2F1, β-Catenin, hepatic tumors, transgenic mouse models
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Elsevier B.V. on behalf of European Association for the Study of the Liver
ISSN:0168-8278
Deposited On:18 Aug 2009 10:04

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