title: Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.
abstract: Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Francheska
authors.initials: F
authors.lastname: Colon-Gonzalez
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Erik
authors.initials: E
authors.lastname: Blomain
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Kim
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Amanda
authors.initials: A
authors.lastname: Aing
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Brian
authors.initials: B
authors.lastname: Stoecker
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Justin
authors.initials: J
authors.lastname: Rock
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Snook
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Terry M
authors.initials: TM
authors.lastname: Hyslop
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, the Biomedical Research Institute, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomczak
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, the Biomedical Research Institute, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania. scott.waldman@jefferson.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D045265:Natriuretic Peptides / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D018000:Receptors, Peptide; C072685:guanylin; C000613654:GUCY2C protein, human; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled