Journal Article

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

Duñach, Mireia, Gonzalez, Sara, Espinosa, Lluís, Robert-Moreno, Àlex, Rodilla, Verónica, Sanjuan, Xavier, Capella, Gabriel, Bellora, Nicolás, Albà, M. Mar, Grilli, Andrea, Bigas, Anna, Fernández-Majada, Vanessa, López-Bigas, Nuria, Villanueva, Alberto, Torres, Ferran, Obrador-Hevia, Antonia, Gridley, Thomas

2009

Overview

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/β-catenin) that are directly regulated by Notch (repressed by γ-secretase inhibitors and up-regulated by active Notch1 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 Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APCMin/⁺ with Jagged1⁺/Δ 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 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adenoma / Alleles / Animals / Antibodies / beta Catenin - metabolism / Biological Sciences / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cancer / carcinogenesis / Cell Line / Cell lines / Cell Nucleus - metabolism / Colorectal cancer / Colorectal carcinoma / colorectal neoplasms / Colorectal Neoplasms - blood supply / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / crossing / Gene expression / Gene Expression Profiling / Gene expression regulation / Gene Expression Regulation, Neoplastic / Genes / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Intestines / Jagged-1 Protein / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, Transgenic / microarray technology / mutants / Mutation / neoplasm cells / patients / Receptors, Notch - metabolism / Rodents / Serrate-Jagged Proteins / Signal Transduction / Stem cells / TCF Transcription Factors - metabolism / Transcription, Genetic - genetics / transcriptional activation / Tumors / Wnt Proteins - metabolism