Vitamin D Receptor Upregulates Tight Junction Protein Claudin-5 against Tumorigenesis

Abstract

Background/ObjectiveTight junctions (TJs) are essential for barrier integrity, inflammation, and cancer. The TJ protein Claudin-5 in the epithelia forms paracellular barriers and pores for permeability. Vitamin D and the vitamin D receptor (VDR) play important roles in various cancers. Although VDR and Claudin-5 are all involved in colorectal cancer (CRC), it remains unclear if they are closely related or function independently. DesignUsing the human CRC database, we explored the correlation between VDR and Claudin-5. We then investigated the VDR regulation of Claudin-5 using VDR knockout (VDR-/-) and intestinal epithelial VDR knockout mice (VDR{Delta}IEC) with chemical-induced colon cancer and an epithelial VDR overexpression model. Human samples, organoids, and intestinal epithelial cells were used to determine the underlying mechanisms. ResultsIn human colon cancer, colonic VDR expression was low and was significantly correlated with a reduction of Claudin-5 mRNA and protein. In the colon of VDR-/- and VDR{Delta}IEC mice, deletion of VDR led to lower protein and mRNA levels of Claudin-5. Intestine permeability was increased in the AOM-DSS-induced VDR-/- colon cancer model. Lack of VDR and a reduction of Claudin-5 are associated with an increased number of tumors in the VDR-/- and VDR{Delta}IEC mice. Furthermore, gain and loss of function studies have identified CLDN-5 as a downstream target of the VDR signaling pathway. Epithelial VDR overexpression protected against the loss of Claudin 5 in response to intestinal inflammation ConclusionThis study advances the understanding of how VDR regulates intestinal barrier functions in tumorigenesis as a biomarker and potential treatment. A short summaryO_LIWhat is already known about this subject? O_LITight junction structures are essential for intestinal barrier integrity, inflammation, and cancer. C_LIO_LIVitamin D deficiency and the vitamin D receptor (VDR) play important roles in the development of colon cancer. C_LI C_LIO_LIWhat are the new findings? O_LIOur study is the first to link barrier function, a specific tight junction protein, and genetic susceptibility through intestinal epithelial VDR in human colorectal cancer. C_LIO_LIOur study fills an existing gap by characterizing the mechanism of intestinal epithelial VDR in regulating barrier functions through alterations in TJs in tumorigenesis. VDR is important for the maintenance of the physiological level of the TJ protein Claudin-5 in the colon. The CLDN-5 gene is a downstream target of the VDR signaling pathway. Lack of VDR led to a reduction of Claudin-5 in tumors, whereas enhancing VDR increased Claudin-5 to protect the intestinal epithelial cells from tumorigenesis. C_LIO_LIWe report fecal VDR reduction in a colon cancer model. This introduces the possibility for the identification of new biomarkers and therapeutic targets to restore VDR-dependent functions in CRC. C_LI C_LIO_LIHow might it impact on clinical practice in the foreseeable future O_LIDiagnosis of CRC considering VDR status C_LIO_LIBarrier: direct, indirect biomarkers C_LIO_LIIntestinal barriers in cancer prevention and treatment C_LI C_LI Barrier function and VDR are not only essential for the maintenance of intestinal homeostasis, but they are also critical for the development of chronic mucosal inflammation and cancer. This knowledge can be immediately used to develop intestinal VDR and Claudin-5 as clinical biomarkers for identifying patients who may benefit from currently available interventions and could also be used for the eventual development of novel strategies for the prevention and treatment of human CRC.