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.
Highlights
The mucosal surface of the intestinal tract is covered with a single layer of epithelium that constitutes a physical and immunological barrier against a variety of foreign antigens derived from food, pathogens and commensal bacteria
Notch promotes the absorptive fate through upregulation of the transcriptional repressor hairy and enhancer of split-1 (Hes-1), which, in turn inhibits the expression of atonal homolog-1 (Atoh1), a master transcription factor for all secretory cells [11]
We show that the Villin-Cre/Notch-1fl/fl (VN-/-) mice, which have a deletion of Notch-1 under the villin promoter in the intestinal epithelial cells, develop serrated lesions, multifocal epithelial dysplasia and spontaneous colorectal mucinous neoplasms in a background of colonic mucosa with impaired barrier integrity, and enhanced goblet cell metaplasia
Summary
The mucosal surface of the intestinal tract is covered with a single layer of epithelium that constitutes a physical and immunological barrier against a variety of foreign antigens derived from food, pathogens and commensal bacteria. The Notch signaling pathway plays a key role in the embryonic and adult gut epithelium, and is required both for maintenance of intestinal stem cells and for a proper balance of differentiation between secretory and absorptive cell lineages [7, 8]. Blocking Notch signaling with γ-secretase inhibitors or by deletion of the Notch effector recombinant binding protein suppressor of hairless (RBP-J) induces loss of proliferating stem and progenitor cells, and a global secretory cell hyperplasia in the intestine of mice [9, 10]. Transgenic expression of a constitutively active form of Notch-1, the intracellular domain of Notch (NICD), in the intestinal epithelium affects the amplification of immature progenitor cells at the expense of secretory cells [13, 14]
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