Indeed, genetic or chemical disruption of the intestinal barrier associated with inflammation produces systemic DNA damage and genotoxic stress, including in circulating leukocytes. Here, barrier disruption and hyperpermeability produced by silencing GUCY2C was associated with elevated levels of oxidative DNA damage in circulating leukocytes. Conversely, defending barrier integrity and restricting permeability by activating GUCY2C with oral ST decreased systemic genotoxicity in hepatocytes produced by DSS. Further, systemic genotoxicity produced by barrier disruption reflecting GUCY2C silencing was associated with increased spontaneous and carcinogen-induced extra-intestinal tumorigenesis, specifically in lung, liver and lymph nodes. In the context of the role of GUCY2C as a tissue-specific tumor suppressing receptor, the present observations expand that function beyond transformation in the colorectum, to neoplasia in lymph nodes, liver, and lung through maintenance of epithelial barrier integrity. Moreover, it is tempting to speculate that loss of paracrine hormone expression and silencing of GUCY2C in inflammatory bowel disease produces systemic genotoxicity which contributes to the pattern of extra-intestinal cancer in these patients specifically in lymph nodes, liver,Herbacetin and lung. The present study further clarifies the evolving role of the GUCY2C paracrine hormone system in modulating the intestinal barrier. A role for GUCY2C in regulating epithelial barrier function was recently demonstrated, and the present work confirms that phenomenon. Those studies revealed that silencing GUCY2C disrupted the barrier and induced inflammation, associated with production of interferon gamma and IL-12. In turn, those events were associated with increased expression of epithelial cell myosin light chain kinase, an established regulator of tight junction structure and function, and suppression of JAM-A and claudin 2 expression. These phenomena were presumed to be the molecular mechanisms mediating GUCY2C-dependent barrier disruption. However, canonical regulation of myosin light chain phosphorylation by cGMP is mediated by myosin light chain phosphatase, rather than myosin light chain kinase. Moreover, these observations are complicated by the contribution of inflammatory cytokines,Diosgenin-glucoside including interferon gamma, to regulation of expression of myosin light chain kinase in intestinal epithelial cells in vivo and in vitro. Thus, the contribution of these components may not reflect the primary mechanism underlying GUCY2C regulation of barrier integrity but, rather, an epiphenomenon related to the associated inflammation. In contrast, the present study demonstrates a mechanistic role for GUCY2C as a primary modulator of the intestinal epithelial barrier, mediated by AKT1, occludin and claudin 4, but not JAM-A and claudin 2, in mouse models in vivo, and in human intestinal cell monolayers in vitro in the absence of confounding by inflammation. Paradoxically, subsequent work from the same group suggested that eliminating GUCY2C signaling protects the intestinal mucosa from inflammatory injury. Beyond proliferation, metabolism, and chromosomal integrity, the present studies reveal an additional dimension of AKT1dependent epithelial homeostatic regulation by GUCY2C. Indeed, it is tempting to speculate that one essential function of GUCY2C signaling is maintenance of intestinal barrier integrity. In that context, regulation of epithelial tight junctions contributing to macromolecular permeability described here can be added to other established GUCY2C functions, including fluid and electrolyte secretion accelerating lumenal clearance; differentiation of Paneth cells producing antimicrobial peptides; and differentiation of goblet cells producing intestinal mucus that contribute to the separation of systemic and environmental compartments across the mucosal interface.