Abstract 5741: GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity

Abstract

Abstract Background & Aims. The barrier separating mucosal and systemic compartments is formed by tight junctions annealing epithelial cells together, which limit paracellular exchange that threatens compartmental homeostasis. 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. Methods. Gucy2c−/− and villinERT2-ROSA-Guca2a mouse models, as well as in vivo ligand supplementation models were examined for tight junction structure by expression profile, electron microscopy, and immunoblot analysis. Barrier integrity was quantified by oral FITC-dextran after barrier disruption with DSS. Systemic genotoxicity and tumorigenesis were examined in mice with and without GUCY2C signaling. The role of AKT in tight junction regulation was examined in Akt+/− mice and in Caco2 cells using shRNA or AKT mutants. Results. Gucy2c−/− mice exhibited disrupted tight junctions, associated with reduced junctional proteins and barrier hyperpermeability. Conversely, ligand activation of GUCY2C in mice increased junctional proteins and reduced barrier permeability. Further, eliminating GUCY2C exacerbated, while activation reduced, DSS-induced barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, oxidative DNA damage and tumorigenesis in lymph nodes, liver and lung. GUCY2C regulated barrier integrity by repressing AKT1 which increased the junction proteins occludin and claudin 4 in mice and Caco2 cells. Conclusions. GUCY2C defends the intestinal barrier, restricting permeability to maintain homeostasis in mucosal and systemic compartments. The pathophysiological significance of GUCY2C-dependent barrier protection is highlighted by its impact on colitis and systemic genotoxicity and tumorigenesis in multiple organs. Its translational potential is underscored by the imminent regulatory approval of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5741. doi:1538-7445.AM2012-5741