Upregulated Claudin-1 Expression Promotes Colitis-associated Cancer by promoting β-Catenin phosphorylation and activation in Notch/p-AKT Dependent Manner

In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1(Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice is used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and underlying mechanism using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation, defective epithelial homeostasis accompanied the increased CAC in Villin-Cld1-Tg mice. We further found significantly increased levels of pro-tumorigenic M2 macrophages and β-CateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg versus WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1 dependent activation of the β-CatSer552, which, in turn, was dependent on pro-inflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its non-canonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.