Knockdown of Sodium-Calcium Exchanger 1 Induces Epithelial to Mesenchymal Transition in Kidney Epithelial Cells [Cell Biology]

Mesenchymal to epithelial transition (MET) and epithelial to mesenchymal transition (EMT) are important processes in kidney development. Failure to undergo MET during development leads to the initiation of Wilms tumor (WT) whereas EMT contributes to the development of renal cell carcinomas (RCC). The role of calcium regulators in governing these processes is becoming evident. We demonstrated earlier that Na+/Ca2+ exchanger 1 (NCX1), a major calcium exporter in renal epithelial cells, regulates epithelial cell motility. Here, we show for the first time that NCX1 mRNA and protein expression was downregulated in WT and RCC. Knockdown of NCX1 in MDCK cells induced fibroblastic morphology, increased inter-cellular junctional distance, induced paracellular permeability, loss of apico-basal polarity in three-dimensional cultures, and anchorage independent growth, accompanied by expression of mesenchymal markers. We also provide evidence that NCX1 interacts with and anchors E-cadherin to the cell surface independent of NCX1 ion transport activity. Consistent with destabilization of E-cadherin, NCX1 knockdown cells showed an increase in β-catenin nuclear localization, enhanced transcriptional activity and upregulation of downstream targets of β-catenin signaling pathway. Taken together, knockdown of NCX1 in MDCK cells alters epithelial morphology and characteristics by destabilization of E-cadherin and induction of β-catenin signaling.

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