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Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma

David Dunkin1,2, Alina C Iuga3, Sanda Mimouna4,5,6

  • 1Department of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Oncotarget
|October 17, 2018
PubMed

Insights

Notch-1 signaling is crucial for maintaining intestinal health. Loss of Notch-1 in intestinal cells promotes goblet cell hyperplasia and leads to colorectal mucinous adenocarcinomas in mice, revealing its protective role against intestinal tumorigenesis.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Oncology

Background:

  • Notch-1 signaling maintains intestinal architecture and homeostasis.
  • Dysfunction in RBP-J, a Notch-1 pathway transcription factor, impairs epithelial barrier integrity and promotes goblet cell conversion.
  • Epithelial Notch-1 is vital for gut immunity and pro-inflammatory responses.

Purpose of the Study:

  • To investigate the epithelial-specific role of Notch-1 in intestinal tumorigenesis.
  • To determine if Notch-1 deficiency in intestinal epithelial cells contributes to colorectal cancer development.

Main Methods:

  • Generation of Villin-Cre/Notch-1 (VN) mice with selective Notch-1 deficiency in intestinal epithelial cells.
  • Histopathological analysis of intestinal tissues to assess barrier function, cell differentiation, and lesion development.
  • Evaluation of gene expression related to tumor promotion and comparison of Notch-1 expression in human colorectal tumors.

Main Results:

  • Loss of epithelial Notch-1 led to goblet cell hyperplasia, serrated lesions, and dysplasia in mice.
  • VN mice developed high-grade colonic mucinous neoplasms and colorectal mucinous adenocarcinomas.
  • Tumorigenesis correlated with increased expression of mitogenic, angiogenic, and pro-tumorigenic genes.
  • Human colorectal mucinous adenocarcinoma showed reduced Notch-1 expression compared to adenocarcinoma.

Conclusions:

  • Epithelial Notch-1 plays a critical protective role in preventing intestinal tumorigenesis.
  • Reduced Notch-1 expression is associated with human colorectal mucinous adenocarcinoma.
  • Targeting Notch-1 signaling may offer a therapeutic strategy for colorectal cancer.
Keywords:
Notch-1colorectal cancermucinous adenocarcinoma

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