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Suppression of Calcium Entry Modulates the Expression of TRβ1 and Runx2 in Thyroid Cancer Cells, Two Transcription
Muhammad Yasir Asghar1,2, Taru Knuutinen2,3, Emilia Holm3
1Cell and Tissue Dynamics Research Program, Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 9, FI-00014 Helsinki, Finland.
Abstract:
The thyroid hormone receptor beta 1 (TRβ1) is downregulated in several human cancer cell types, which has been associated with development of an aggressive tumor phenotype and the upregulation of Runt-related transcription factor 2 (Runx2). In this study, we show that the expression of TRβ1 protein is downregulated in human thyroid cancer tissues and cell lines compared with the normal thyroid tissues and primary cell line, whilst Runx2 is upregulated under the same conditions. In contrast, the expression of TRβ1 is upregulated, whereas Runx2 is downregulated, in STIM1, Orai1 and TRPC1 knockdown cells, compared to mock transfected cells. To study the functional significance of Runx2 in follicular thyroid cancer ML-1 cells, we downregulated it by siRNA. This increased store-operated calcium entry (SOCE), but decreased cell proliferation and invasion. Moreover, restoring TRβ1 expression in ML-1 cells decreased SOCE, basal and sphingosine 1-phosphate (S1P)-evoked invasion, the expression of the promigratory S1P3 receptor and pERK1/2, and at the same time increased the expression of the thyroid specific proteins thyroglobulin, thyroperoxidase, and thyroid transcription factor-1. In conclusion, we show that TRβ1 is downregulated in thyroid cancer cells and that restoration of its expression can reverse the cancer cell phenotype towards a normal thyroid cell phenotype.
Insights
Thyroid hormone receptor beta 1 (TRβ1) downregulation in thyroid cancer correlates with aggressive tumors. Restoring TRβ1 expression reverses cancer cell phenotype toward normal, reducing invasion and increasing thyroid-specific proteins.
Area of Science:
- Endocrinology
- Cancer Biology
- Molecular Biology
Background:
- Thyroid hormone receptor beta 1 (TRβ1) downregulation is linked to aggressive cancer phenotypes and Runt-related transcription factor 2 (Runx2) upregulation.
- TRβ1 expression is reduced, while Runx2 expression is elevated in human thyroid cancer tissues and cell lines.
Purpose of the Study:
- To investigate the functional significance of Runx2 in follicular thyroid cancer.
- To determine the effects of TRβ1 restoration on cancer cell phenotype and related molecular pathways.
Main Methods:
- siRNA-mediated knockdown of Runx2 in ML-1 cells.
- Analysis of store-operated calcium entry (SOCE), cell proliferation, and invasion.
- Restoration of TRβ1 expression in ML-1 cells and assessment of its impact on SOCE, invasion, receptor expression, and thyroid-specific protein levels.
Main Results:
- Runx2 downregulation in ML-1 cells increased SOCE but decreased proliferation and invasion.
- Restoring TRβ1 expression reduced SOCE, invasion (basal and S1P-evoked), S1P3 receptor, and pERK1/2 levels.
- TRβ1 restoration increased the expression of thyroglobulin, thyroperoxidase, and thyroid transcription factor-1.
Conclusions:
- TRβ1 is downregulated in thyroid cancer, associated with an aggressive phenotype.
- Restoration of TRβ1 expression can revert cancer cells towards a normal thyroid cell phenotype, offering potential therapeutic implications.
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