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Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

2009; National Academy of Sciences; Volume: 106; Issue: 15 Linguagem: Inglês

10.1073/pnas.0813221106

1091-6490

Verónica Rodilla, Alberto Villanueva, Antònia Obrador‐Hevia, Alexandre Robert‐Moreno, Vanesa Fernández‐Majada, Andrea Grilli, Núria López-Bigas, Nicolás Bellora, M. Mar Albà, Ferrán Torres, Mireia Duñach, Xavier Sanjuán, Sara González, Thomas Gridley, Gabriel Capellà, Anna Bigas, Lluı́s Espinosa,

Genetic factors in colorectal cancer

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(Min/+) with Jagged1(+/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.