Stromal Interaction Molecule 1 (STIM1) Knock-down Attenuates Migration and Proliferation and Enhances the Expression of Thyroid Specific Proteins in Human Follicular Thyroid Cancer Cells.

Abstract Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remained elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared with primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced migration, and expression of promigratory sphingosine 1-phosphate (S1P) and vascular endothelial growth factor-2 (VEGFR2) receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared with normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor (TSHR), thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated migration and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer.