Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

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.

Recombinant Human TSH Fails to Induce the Proliferation and Migration of Papillary Thyroid Carcinoma Cell Lines

“…( Figure 1d ). This low expression has also been verified by other groups [23,27,28,40]; while some others even cite TSHR expression as undetectable [41–43]. Low TSHR expression allows only for limited stimulation by circulating TSH molecules and this was theorized to be a great limitation of the hormone’s role study.…”

“…Herein, we investigated for the first time the effects of rh-TSH in physiologically relevant doses resembling the TSH concentrations in human plasma on the function and proliferation of PTC human thyroid cell lines. For this purpose, we selected two well established cell lines, K1 and TPC-1, both of which adequately model PTC cells and express the main thyroid markers, thus allowing their classification as PTC cells and indicting their differentiation status [27,28]. To fully assess the role of rh-TSH in PTC cell proliferation, not only did we co-administer it with recombinant human insulin (rh-INS), but we also created cells that controllably overexpress the TSH receptor.…”

The Mysterious Universe of the TSH Receptor

“…TSH has also been shown to promote vascular endothelial growth factor production thus contributing to angiogenesis ( 75 , 76 ) to induce genomic instability ( 77 ) and to contribute to invasion and immune evasion in thyroid tumors ( 78 ). Conversely, the TSH-R seems to have an important role in maintaining differentiation of thyroid cancer cells, and in advanced and dedifferentiated thyroid cancer, a decrease in its expression has commonly been reported ( 79 ).…”

Puerarin inhibits inflammation and oxidative stress in female BALB/c mouse models of Graves’ disease

“…Among these effector molecules, AKT is the most studied and universally activated molecule downstream of PI3Ks ( 9 ). Studies have reported that TSAb can regulate the proliferation activity of thyroid cells via the PI3K/AKT pathway ( 10 , 11 ). Chinese medicine for hyperthyroidism primarily modulates the proliferation and apoptosis of thyroid cells through regulation of the PI3K/AKT pathway to effectively treat GD ( 12 - 14 ).…”