BACKGROUND/AIMS: 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. 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 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-3beta 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. CONCLUSIONS: The data demonstrate that 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.
BACKGROUND/AIMS: Previously, we showed that activation of the beta-catenin/Wnt pathway is a dominant event during c-Myc/E2F1hepatocarcinogenesis. 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/E2F1hepatocarcinogenesis. 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 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-3beta 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. CONCLUSIONS: The data demonstrate that 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.
Authors: Galina A Gusarova; I-Ching Wang; Michael L Major; Vladimir V Kalinichenko; Timothy Ackerson; Vladimir Petrovic; Robert H Costa Journal: J Clin Invest Date: 2006-12-14 Impact factor: 14.808
Authors: Mohammed A F Elewa; Mohammed M Al-Gayyar; Mona F Schaalan; Khaled H Abd El Galil; Mohamed A Ebrahim; Mamdouh M El-Shishtawy Journal: Clin Exp Metastasis Date: 2015-05-22 Impact factor: 5.150
Authors: Sven Schneider; Philipp Kloimstein; Johannes Pammer; Werner Brannath; Matthaeus Ch Grasl; Boban M Erovic Journal: Eur Arch Otorhinolaryngol Date: 2013-10-04 Impact factor: 2.503