title: GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.
abstract: The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jieru Egeria
authors.initials: JE
authors.lastname: Lin
authors.forename: Adam Eugene
authors.initials: AE
authors.lastname: Snook
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Brian Arthur
authors.initials: BA
authors.lastname: Stoecker
authors.forename: Gilbert Won
authors.initials: GW
authors.lastname: Kim
authors.forename: Michael Sullivan
authors.initials: MS
authors.lastname: Magee
authors.forename: Alex Vladimir Mejia
authors.initials: AV
authors.lastname: Garcia
authors.forename: Michael Anthony
authors.initials: MA
authors.lastname: Valentino
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.forename: Scott Arthur
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D062506:Claudin-4; D057167:Claudins / Q000235:genetics; D003092:Colitis; D004249:DNA Damage; D005260:Female; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens; D062793:Occludin; D010539:Permeability; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; D057167:Claudins; C568158:Cldn4 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D009153:Mutagens; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D018000:Receptors, Peptide; D051057:Proto-Oncogene Proteins c-akt; C000613654:GUCY2C protein, human; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled