Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma

David Dunkin, Alina C. Iuga, Sanda Mimouna, Carolyn L. Harris, Jean Vianney Haure-Mirande, Dominique Bozec, Garabet Yeretssian, Stephanie Dahan

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Increasing evidence links Notch-1 signaling with the maintenance of intestinal architecture and homeostasis. Dysfunction in the common Notch-1 pathway transcription factor recombinant binding protein suppressor of hairless (RBP-J) is associated with loss of epithelial barrier integrity and aberrant conversion of proliferative crypt cells into goblet cells. Furthermore, we have recently discovered that epithelial Notch-1 is indispensable in bridging innate and adaptive immunity in the gut and is required for supporting protective epithelial pro-inflammatory responses. Yet, the epithelial specific function of Notch-1 in intestinal tumorigenesis remains unknown. We generated Villin-Cre/Notch-1fl/fl (VN-/-) mice that are selectively deficient in Notch-1 in intestinal epithelial cells. Intestinal epithelial Notch-1 preserved barrier function and integrity, whereas lack of epithelial Notch-1 induced goblet cell hyperplasia, spontaneous serrated lesions, multifocal low-and high-grade dysplasia and colonic mucinous neoplasms in mice. Over time, VN-/- mice displayed high occurrence of colorectal mucinous adenocarcinomas, which correlated with increased levels of mitogenic, angiogenic and pro-tumorigenic gene expression. Finally, we found that the expression of Notch-1 is significantly reduced in human colorectal mucinous adenocarcinoma when compared to colorectal adenocarcinoma. Taken together, our findings reveal a novel and critical protective role for Notch-1 in controlling intestinal tumorigenesis.

Original languageEnglish
Pages (from-to)33536-33548
Number of pages13
JournalOncotarget
Volume9
Issue number71
DOIs
StatePublished - 1 Sep 2018

Keywords

  • Colorectal Cancer
  • Mucinous Adenocarcinoma
  • Notch-1

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