Article

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

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.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2009; 106(15):6315-20. DOI: 10.1073/pnas.0813221106
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
192 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In a tumor cell, the development of acquired therapeutic resistance and the ability to survive in extracellular environments that differ from the primary site are the result of molecular adaptations in potentially highly plastic molecular networks. The accurate prediction of intracellular networks in a tumor remains a difficult problem in cancer informatics. In order to make truly rational patient-driven therapeutic decisions, it will be critical to develop methodologies that can accurately infer the molecular circuitry in the cells of a specific tumor. Despite enormous heterogeneity, cellular networks elicit deterministic digital-like responses. We discuss the use and limitations of methodologies that model molecular networks in cancer cells as a digital circuit. We also develop a network model of Notch signaling in colon cancer using a novel reverse engineering logic-based method and published western blot data to elucidate the interactions likely present in the circuits of the SW480 colon cancer cell line. Within this framework, we make predictions related to the role that honokiol may be playing as an anti-cancer drug.
    Cancer informatics 01/2014; 13(Suppl 5):1-12. DOI:10.4137/CIN.S14060
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal. © 2015. Published by The Company of Biologists Ltd.
    Development 01/2015; 142:41-50. DOI:10.1242/dev.107714 · 6.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the intestinal epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of intestinal epithelium homeostasis by regulating Notch activity.
    Cell Death & Disease 02/2015; 6(2):e1631. DOI:10.1038/cddis.2014.588 · 5.18 Impact Factor

Full-text (2 Sources)

Download
681 Downloads
Available from
May 31, 2014