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

¹ Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas; ² Departments of Medicine, Physiology, and Human Genetics, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada; and ³ Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

Requests for reprints: Subhas Chakrabarty, Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-5538; Fax: 713-792-4606; E-mail: schakrab{at}mdanderson.org..

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.

Key Words: calcium • calcium sensing receptor • 1,25-dihydroxyvitamin D₃ • colon carcinoma

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