Jutta Maria Nagel1, Harald Lahm2,3, Andrea Ofner4, Burkhard Göke4,5, Frank Thomas Kolligs4,6. 1. Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. Jutta.Nagel@med.uni-muenchen.de. 2. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian University of Munich (LMU), Feodor-Lynen-Strasse 25, 81377, Munich, Germany. 3. Department of Cardiovascular Surgery, Division of Experimental Surgery, German Heart Center Munich, Technical University (TU), Munich Heart Alliance, Lazarettstraße 36, 80636, Munich, Germany. 4. Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. 5. University Hospital Hamburg-Eppendorf (UKE), Martinistraße 52, 20246, Hamburg, Germany. 6. Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125, Berlin, Germany.
Abstract
PURPOSE: γ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. METHODS: γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. RESULTS: γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule β-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. CONCLUSIONS: This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.
PURPOSE: γ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. METHODS: γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. RESULTS: γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule β-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. CONCLUSIONS: This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.
Authors: Asta Varis; Maija Wolf; Outi Monni; Marja-Leena Vakkari; Arto Kokkola; Chris Moskaluk; Henry Frierson; Steven M Powell; Sakari Knuutila; Anne Kallioniemi; Wa'el El-Rifai Journal: Cancer Res Date: 2002-05-01 Impact factor: 12.701
Authors: Svetlana Mukhina; Hichem C Mertani; Ke Guo; Kok-Onn Lee; Peter D Gluckman; Peter E Lobie Journal: Proc Natl Acad Sci U S A Date: 2004-09-07 Impact factor: 11.205
Authors: Jutta Maria Nagel; Lydia Kriegl; David Horst; Jutta Engel; Shiva Gautam; Christos S Mantzoros; Thomas Kirchner; Burkhard Göke; Frank Thomas Kolligs Journal: Int J Colorectal Dis Date: 2010-08-25 Impact factor: 2.571