Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis

Tight junctions are essential for barrier integrity, inflammation, and cancer. Vitamin D and the vitamin D receptor (VDR) play important roles in colorectal cancer (CRC). Using the human CRC database, we found colonic VDR expression was low and significantly correlated with a reduction of Claudin-5 mRNA and protein. In the colon of VDR^ΔIEC mice, deletion of intestinal VDR led to lower protein and mRNA levels of Claudin-5. Intestinal permeability was increased in the VDR^-/- colon cancer model. Lacking VDR and a reduction of Claudin-5 are associated with an increased number of tumors in the VDR^-/- and VDR^ΔIEC mice. Furthermore, gain and loss functional studies have identified CLDN-5 as a downstream target of VDR. We identified the Vitamin D response element (VDRE) binding sites in a reporter system showed that VDRE in the Claudin-5 promoter is required for vitamin D₃-induced Claudin-5 expression. Conditional epithelial VDR overexpression protected against the loss of Claudin-5 in response to inflammation and tumorigenesis in vivo. We also reported fecal VDR reduction in a colon cancer model. This study advances the understanding of how VDR regulates intestinal barrier functions in tumorigenesis and the possibility for identifying new biomarker and therapeutic targets to restore VDR-dependent functions in CRC.