Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

Abstract

Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that dietinduced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorieinduced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

Immunohistochemical Staining for Uroguanylin, a Satiety Hormone, is Decreased in Intestinal Tissue Specimens From Female Adolescents With Obesity

“…But overall, GUCY2C expression appears to be stable in obesity as compared to average BMI-for-age specimens, both within pairs and between cohorts. The implication is that the effects of obesity center on the signaling peptides and not the downstream receptor, echoing observations in animal models, 29,37,38 and recent studies in adults with obesity. 30 Our study has limitations.…”

Pilot Study Measuring the Novel Satiety Hormone, Pro‐Uroguanylin, in Adolescents With and Without Obesity

“…28 In obesity, uroguanylin expression is suppressed or lost, 32 altering satiety; thus the uroguanylin-GUCY2C system is at the intersection of obesity pathogenesis and sequelae. 33–35…”

The most important questions in cancer research and clinical oncology—Question 2–5. Obesity-related cancers: more questions than answers

“…Some explanations for “adiponcosis” are site-specific—for example, esophageal adenocarcinomas due to reflux and Barret’s esophagus; breast cancer due to raised estrogens generated from fatty tissue via aromatase enzyme; liver cancer due to NAFLD; and gallbladder cancer due to higher incidence of gallstones. A recent study suggested that an excess of calories suppress GUCY2C signaling (a tumor suppressor gene), resulting in intestinal tumorigenesis in obesity [ 77 , 78 ]. However, no single unifying explanation has been found to be satisfactory.…”