Jagged1 is the pathological link between Wnt and Notch pathways 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.
Rodilla
Verónica
V
Institut d'Investigació Biomèdica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'Investigacions Mèdiques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain.
Villanueva
Alberto
A
Obrador-Hevia
Antonia
A
Robert-Moreno
Alex
A
Fernández-Majada
Vanessa
V
Grilli
Andrea
A
López-Bigas
Nuria
N
Bellora
Nicolás
N
Albà
M Mar
MM
Torres
Ferran
F
Duñach
Mireia
M
Sanjuan
Xavier
X
Gonzalez
Sara
S
Gridley
Thomas
T
Capella
Gabriel
G
Bigas
Anna
A
Espinosa
Lluís
L