Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.
Alleles, Animals, Calcium-Binding Proteins, Cell Line, Cell Nucleus, Colorectal Neoplasms, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Intercellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Transgenic, Receptors, Notch, Signal Transduction, TCF Transcription Factors, Transcription, Genetic, Wnt Proteins, beta Catenin
National Academy of Sciences
Proc Natl Acad Sci U S A 2012 Apr 14; 106(15):6315-20.
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; Villanueva, Alberto; Obrador-Hevia, Antonia; Robert-Moreno, Alex; Fernández-Majada, Vanessa; Grilli, Andrea; López-Bigas, Nuria; Bellora, Nicolás; Albà, M Mar; Torres, Ferran; Duñach, Mireia; Sanjuan, Xavier; Gonzalez, Sara; Gridley, Thomas; Capella, Gabriel; Bigas, Anna; and Espinosa, Lluís, "Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer." (2009). Faculty Research 2000 - 2009. 1948.