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Regulation of E-cadherin and beta-catenin by Ca2+ in colon carcinoma is dependent on calcium-sensing receptor
Narasimharao Bhagavathula1, Andrew W Hanosh, Kamalakar C Nerusu
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Abstract:
An siRNA directed against the extracellular calcium-sensing receptor (CaSR) was used to down-regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellular Ca(2+). In neither the siRNA-transfected cells nor the Ca(2+)-nonresponsive variant cells did inclusion of Ca(2+) in the culture medium inhibit proliferation or induce morphological alterations. Extracellular Ca(2+) also failed to induce E-cadherin production or a shift in beta-catenin from the cytoplasm to the cell membrane. In mock-transfected cells and in a Ca(2+)-responsive variant line derived from the same parental CBS cells, Ca(2+) treatment resulted in growth-reduction. This was accompanied by increased E-cadherin production and a shift in beta-catenin distribution from the cytoplasm to the cell membrane. Additionally, down-regulation of c-myc and cyclin D1 expression was observed in mock-transfected cells and in the Ca(2+)-responsive variant line (along with reduced T cell factor transcriptional activation). Neither c-myc nor cyclin D1 was significantly down-regulated in the siRNA-transfected cells or in the Ca(2+)-nonresponsive variant cells upon Ca(2+) stimulation. In histological sections of human colon carcinoma CaSR was significantly reduced as compared to the level in normal colonic crypt epithelial cells. Where CaSR expression was high, strong surface staining for E-cadherin and beta-catenin was observed. Where CaSR expression was reduced, beta-catenin surface expression was likewise reduced.
Insights
Extracellular calcium-sensing receptor (CaSR) down-regulation impairs colon cancer cell response to calcium. Reduced CaSR in colon tumors correlates with lower E-cadherin and beta-catenin, impacting cell adhesion and growth regulation.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- The extracellular calcium-sensing receptor (CaSR) plays a role in cellular homeostasis.
- CaSR's function in colon carcinoma proliferation and cell-cell adhesion is not fully understood.
Purpose of the Study:
- To investigate the role of CaSR in colon carcinoma cell proliferation, morphology, and expression of key proteins like E-cadherin and beta-catenin.
- To examine the correlation between CaSR expression levels and these cellular characteristics in human colon carcinoma tissues.
Main Methods:
- Utilized siRNA to down-regulate CaSR in CBS colon carcinoma cells.
- Employed a Ca(2+)-nonresponsive variant and mock-transfected cells for comparative studies.
- Analyzed cell proliferation, morphology, E-cadherin, beta-catenin, c-myc, and cyclin D1 expression.
- Examined CaSR, E-cadherin, and beta-catenin expression in human colon carcinoma histological sections.
Main Results:
- Ca(2+) treatment inhibited proliferation and induced morphological changes in CaSR-expressing, responsive cells, but not in CaSR-down-regulated or nonresponsive cells.
- Ca(2+) induced E-cadherin production and beta-catenin translocation to the cell membrane in responsive cells.
- CaSR down-regulation or nonresponsiveness prevented Ca(2+)-induced c-myc and cyclin D1 suppression.
- Human colon carcinomas showed reduced CaSR compared to normal tissue, with high CaSR correlating with strong E-cadherin and beta-catenin surface expression.
Conclusions:
- CaSR is crucial for mediating the anti-proliferative and cell-adhesion-promoting effects of extracellular calcium in colon cancer cells.
- Reduced CaSR expression in colon tumors may contribute to altered cell adhesion and potentially uncontrolled proliferation.
- Targeting CaSR could represent a therapeutic strategy for colon cancer.
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