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

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.