Abstract 4633: Upregulated claudin-2 expression in ulcerative colitis protects from colitis-associated cancer
Authors: Rizwan Ahmad*, Balawant Kumar*, Narendra Kumar, Ishwor Thapa, Kiran D. Bastola, Mary Kay. Washington, Punita Dhawan, Amar B. Singh
Journal: Cancer Research (2019)

Abstract A link between chronic inflammation and colon cancer has long been appreciated. Accordingly, patients with inflammatory bowel (IBD) are at higher risk for developing colitis-associated cancer (CAC). Mucosal barrier dysregulation allies with inflammation and accordingly claudin-2, a tight junction protein, is upregulated in IBD and CAC, and believed to assist in disease progression. Remarkably, recent studies, including ours, using mice manipulated for claudin-2 expression challenge such a belief as claudin-2 transgenic (Cldn-2TG) mice are protected from colitis while Cldn-2KO mice have severe disease. Immune adaptation and mucosal healing appear to help mediate claudin-2 dependent protection from colitis. Of note, claudin-2 expression is restricted to the crypt base and associates with paracellular permeability, differentiation and proliferation. Notably, mucosal healing in IBD patients is associated with decreased risk of CAC. However, a causal role of claudin-2 in progression to the CAC remains unclear. Based on the mice data, we hypothesized that claudin-2 also protects from the CAC. To test this hypothesis, WT and Cldn-2TG mice were subjected to the murine model of AOM/DSS cancer. Indeed, Cldn-2TG mice demonstrated significant protection against the CAC (p&amp;lt;0.001). Both, tumor incidence and growth (p&amp;lt;0.001) were inhibited. High throughput analysis (RNAseq and Cytokine array) demonstrated significant inhibition of the pro-inflammatory signaling in AOM/DSS-treated Cldn-2TG versus WT-mice. In contrast, growth-promoting signaling was upregulated. An in-vitro model of colitis-injury and recovery further demonstrated positive association between claudin-2 expression and cell viability. Based on these findings that increased colonic claudin-2 expression induces an immune suppressive and growth promoting effect, we further postulated a tumor promoting role for claudin-2 in sporadic colon cancer (CRC). Remarkably, offspring mice from the cross between Cldn-2TG and APCmin mice (APCmin/Cldn2TG) demonstrated significant increases in colon tumor burden and progression. RNAseq analysis from these mice further attested to an immune suppressive and growth-promoting effects of increased claudin-2 expression. To further validate, we subjected the APCmin and APCmin/Cldn2TG mice to DSS in drinking water as it potentiates tumor burden in the APCmin mice. Remarkably, DSS-induced potentiation of colon tumorigenesis was significantly lower in the APCmin/Cldn2 mice versus APCmin mice. Taken together, we here report a novel and paradigm-shifting role of claudin-2 in protection against the CAC. Moreover, considering the significant role of the immune signaling in CRC and failure of the effectiveness of immune therapy, our murine models can help understand the dynamics of immune and growth signaling in promoting colon cancer, for therapeutic gains. * Both authors contributed equally Note: This abstract was not presented at the meeting. Citation Format: Rizwan Ahmad*, Balawant Kumar*, Narendra Kumar, Ishwor Thapa, Kiran D. Bastola, Mary Kay. Washington, Punita Dhawan, Amar B. Singh. Upregulated claudin-2 expression in ulcerative colitis protects from colitis-associated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4633.