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, Fernández-Majada, Vanessa, Grilli, Andrea, Lopez-Bigas, Nuria, Bellora, Nicolàs, Albà, M. Mar, Torres, Ferran, Duñach, Mireia, Sanjuan, Xavier, Gonzalez, Sara, Gridley, Thomas, Capella, Gabriel, Bigas, Anna, and Lluís Espinosa
- Subjects
COLON cancer ,NOTCH genes ,WNT genes ,CARCINOGENESIS ,CELL proliferation ,LABORATORY mice - Abstract
Notch has been linked to β-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/β-catenin (down-regulated when blocking Wnt/βcatenin) that are directly regulated by Notch (repressed by γ-secretase inhibitors and up-regulated by active Notchi in the absence of β-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through β-catenin-mediated transcriptional activation of the Notch-ligand Jaggedi. Consistently, expression of activated Notchi partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC[supMinl]with Jagged1[sup+/Δ] miceis 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 β-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by β-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. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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