Abstract
Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses to DNA damage, epithelial-mesenchymal cross-talk, cell migration, and cellular metabolic status. Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer. This review explores the current understanding of cGMP signaling in the intestinal epithelium and mechanisms by which it opposes intestinal injury. Particular focus will be applied to its emerging role in tumor suppression. In colorectal tumors, endogenous GUCY2C ligand expression is lost by a yet undefined mechanism conserved in mice and humans. Further, reconstitution of GUCY2C signaling through genetic or oral ligand replacement opposes tumorigenesis in mice. Taken together, these findings suggest an intriguing hypothesis that colorectal cancer arises in a microenvironment of functional GUCY2C inactivation, which can be repaired by oral ligand replacement. Hence, the GUCY2C signaling axis represents a novel therapeutic target for preventing colorectal cancer.
Highlights
Constituting the largest interface with non-sterile material from the outside world, the intestinal epithelium regulates fluid and nutrient transport, hosts commensal flora, and protects against infiltration by toxins and pathogenic organisms that pass through the digestive tract [1]
The GUCY2C-cyclic GMP (cGMP) signaling axis has emerged as a key regulator of epithelial homeostasis in the intestine
Described as a the regulator of fluid and electrolyte secretion, cGMP is recognized for its roles in modulating epithelial proliferation, DNA integrity, barrier function, microbiome composition, epithelial-mesenchymal cross talk, and other aspects of epithelial function
Summary
Constituting the largest interface with non-sterile material from the outside world, the intestinal epithelium regulates fluid and nutrient transport, hosts commensal flora, and protects against infiltration by toxins and pathogenic organisms that pass through the digestive tract [1] These functions are accomplished by a single-cell layer of columnar epithelial cells, which form a. The surface of the large intestine is relatively smooth (lacking villi), with deep mucus-secreting crypts, enabling fluid absorption and stool transit This crypt-villus axis is a physiologically unique structure, characterized by continuous cell proliferation and turnover. At the base of the crypt, long-lived stem cells give rise to rapidly proliferating daughter cells, which differentiate into specialized epithelial cell subtypes [4] These cells migrate upwards from crypt to villus, differentiating into nutrient-absorbing enterocytes (the majority of the epithelial population), mucus-secreting goblet cells, and hormone secreting enteroendocrine cells [2]. We will conclude with current approaches to targeting this axis for cancer prevention
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