Abstract
Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.
Highlights
Thyroid cancer, over 90% of which is differentiated thyroid cancer (DTC), is one of the most rapidly increasing cancers worldwide
To test our hypothesis that TSH-TSH receptor (TSHR) signaling is associated with the cell migration phenotype in thyroid cancer cells, we performed a wound healing assay in the TPC1, BCPAP and FTC-133 thyroid cancer cell lines grown in medium containing 30 mU/ml TSH, which was observed to induce sufficient TSHR expression (Supplementary Figure S1)
Since Ga12/13 and Gas signaling had the opposite effect in regulating iodide uptake, we investigated the levels of RhoA activation associated with Ga12/13 and cyclic AMP (cAMP) in our cell models of dedifferentiation compared to control cells
Summary
Over 90% of which is differentiated thyroid cancer (DTC), is one of the most rapidly increasing cancers worldwide. 131I therapy remains the firstline treatment for metastatic DTC, and a high level of 131I uptake is a marker of good prognosis [3, 4]. Iodide uptake and thyroid hormone (TH) biosynthesis, vital functions of thyroid cells, are mainly controlled by thyrotropin (TSH) and its receptor (TSHR). Through coupling to Gas and activating the cAMPPKA pathway, TSH-TSHR stimulates the expression of various thyroid-specific genes involved in iodide metabolism, such as thyroglobulin (Tg), thyroperoxidase (TPO) and sodium-iodide symporter (NIS), in turn increasing the iodide uptake of normal or tumorous thyroid cells. T4 withdrawal or rTSH administration is routinely utilized to increase serum TSH levels to facilitate 131I therapy for DTC patients. We hypothesized that the abnormal transduction of downstream TSHR signaling contributes to decreased iodide uptake and is related to the invasion phenotype
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