1. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer
- Author
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Rodilla, Veronica, Villanueva, Alberto, Obrador-Hevia, Antonia, Robert-Moreno, Alex, Fernandez-Majada, Vanessa, Grilli, Andrea, Lopez-Bigas, Nuria, Bellora, Nicolas, Alba, M. Mar, Torres, Ferran, Dunach, Mireia, Sanjuan, Xavier, Gonzalez, Sara, Gridley, Thomas, Capella, Gabriel, Bigas, Anna, and Espinosa, Lluis
- Subjects
Colorectal cancer -- Genetic aspects ,Colorectal cancer -- Development and progression ,Cell proliferation -- Genetic aspects ,Carcinogenesis -- Genetic aspects ,Carrier proteins -- Genetic aspects ,Carrier proteins -- Health aspects ,Cellular signal transduction -- Genetic aspects ,Cellular signal transduction -- Health aspects ,Science and technology - Abstract
Notch has been linked to [beta]-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/[beta]-catenin (down-regulated when blocking Wnt/beta]-catenin) that are directly regulated by Notch (repressed by [gamma]-secretase inhibitors and up-regulated by active Notch1 in the absence of [beta]-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through [beta]-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/[beta]-catenin pathway in tumors implanted s.c. in nude mice. Crossing [APC.sup.MinI+] with [Jagged.sup.1+/[DELTA] mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear [beta]-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by [beta]-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways. beta-catenin | APC | intestine | crosstalk
- Published
- 2009