Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells

Muhammad Yasir Asghar,Van Dien Nguyen,Anna Slita,Christoffer Löf,Ilkka Paatero,You Zhou,Jessica Rosenholm,Kid Törnquist,Pauliina Kronqvist,Jixi Zhang,Taru Lassila

doi:10.1007/s00018-021-03880-0

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 remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced invasion, and the expression of promigratory sphingosine 1-phosphate and vascular endothelial growth factor-2 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 to normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor, 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 invasion 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.

Highlights

Thyroid cancer is the most prevalent endocrine cancer, the incidence and related mortality of which are increasing globally [1]. 95% of thyroid cancer forms arise from follicular cells [2, 3]
We show here that the protein level of Stromal interaction molecule 1 (STIM1) is higher in human follicular and anaplastic cancer cell lines, and that ORAI1 is higher in follicular cancer cell lines, compared with normal human thyroid primary cells (Fig. 1A)
We investigated the importance of the STIM1 and ORAI1 channels in follicular thyroid cancer ML-1 cells, a cell line showing the highest expression of STIM1 and ORAI1 compared to normal human thyroid cells

Summary

Introduction

Thyroid cancer is the most prevalent endocrine cancer, the incidence and related mortality of which are increasing globally [1]. 95% of thyroid cancer forms arise from follicular cells [2, 3]. 95% of thyroid cancer forms arise from follicular cells [2, 3]. The prognosis of thyroid tumors is good. Due to dedifferentiation or genetic mutations, highly aggressive phenotypes arise, which potentiate metastasis of tumor cells mainly to lungs, brain and bones, causing death of the patient within 6 months [4, 5]. Store-operated calcium entry (SOCE) is activated as a result of agonist-evoked emptying of calcium stores in the endoplasmic reticulum (ER). This mechanism results in activation of plasma membrane calcium channels and calcium entry into the cells, ensuring that the calcium stores will be replenished [7]. The calcium signals generated by the SOCE regulate a multitude of cellular functions, including cancer cell proliferation, invasion and migration [8,9,10,11]

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Discussion

Conclusion