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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
Summary
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.
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