Calcium Sensing Receptor in Human Colon Carcinoma: Interaction with Ca2+ and 1,25-Dihydroxyvitamin D3

Abstract

Abstract Recent studies show that the human parathyroid calcium sensing receptor (CaSR) is expressed in human colon epithelium and functions to regulate epithelial proliferation and differentiation. In this study, we show that the cells of the colon crypt acquire CaSR expression as they differentiate and migrate towards the apex of the crypt. CaSR expression was weak in colon carcinomas with a more-differentiated histologic pattern, whereas CaSR expression was undetectable in less-differentiated tumors. We found that Ca2+ and/or 1,25(OH)2D3 stimulated CaSR promoter activity and CaSR protein expression in the human colon carcinoma CBS cells, which possessed a functional CaSR. Both agents concomitantly induced a series of changes in the CBS cells that influence proliferation and differentiation, but cellular responses to the two agents were not identical. Ca2+ strongly induced E-cadherin expression and inhibited the expression of the nuclear transcription factor, TCF4. 1,25(OH)2D3 was weaker in its effect on E-cadherin and was not able to inhibit TCF4 expression. 1,25(OH)2D3 was as strong or stronger than Ca2+ in its induction of the cyclin-dependent kinase inhibitors, P21 and p27. It is concluded that CaSR may function in the colon to regulate epithelial differentiation and that loss of CaSR expression may be associated with abnormal differentiation and/or malignant progression. Extracellular Ca2+ and 1,25(OH)2D3 are potential candidates involved in regulating CaSR expression in the colon and the chemopreventive actions of Ca2+ and 1,25(OH)2D3 in colon cancer may be mediated, in part, through the CaSR.