Abstract
Disclosure: L. Abaandou: None.
Background: Thyroid hormone (TH), T4 and T3, have been shown to trigger pro-proliferative and pro-angiogenic signaling pathways in numerous cancer types through activation of the MAPK signaling pathway, upon binding to a receptor on the extracellular portion of the αVβ3 integrin. In thyroid cancer (TC), high levels of free T4 are associated with malignancy, and high levels of αvβ3 integrin expression correlate with a more aggressive phenotype. Given that thyroid cancer patients are treated with supraphysiologic doses of T4, it is of urgent importance to understand how thyroid cancer cells are affected by these high doses of T4 and to elucidate the involvement of αVβ3 integrin in thyroid cancer malignancy. Methods: The mRNA and/or protein expression of the αV and β3 integrin subunits were assessed in The Cancer Genome Atlas in 496 TCs, commercially available Human Thyroid Cancer Tissue Microarray with 70 TC and 10 normal thyroid tissue samples, and in 14 TC cell lines. CRISPR/Cas9 genome editing was used to knock out the β3 integrin subunit in the TPC1, OCUT2 and FTC133 thyroid cancer cell lines which showed high to moderate αVβ3 expression. Proliferation, migration and invasion assays were carried out in the presence and absence of supraphysiologic doses of thyroid hormones to investigate their effect on these processes, and to confirm the role of TH-αVβ3 signaling. The data were analyzed using GraphPad Prism. Results: Analysis of RNAseq data of 496 TC tissues revealed that both the αV and β3 integrin subunits are expressed in TC. Immunostaining showed a significantly higher αVβ3 expression in papillary TC (p=0.001), and follicular TC (p=0.04), compared to normal thyroid tissue. However, there was not a significant difference in expression between poorly differentiated TC and normal thyroid tissue (p=0.12). Thyroid cancer cells show variable expression of αVβ3, with the TPC1, OCUT2, XTC1 and FTC133 cell lines showing the highest expression. There was no significant difference in the proliferation rate of TPC1 and FTC133 cells treated with T4 (100nM or 1000nM) or T3 (10nM or 100nM), compared to the untreated controls, in monolayer cultures. Similarly, integrin αVβ3 knockout had no significant effect on thyroid cancer cell proliferation. Treatment with T3 did not have a significant effect on cell migration and invasion, while cells with high αVβ3 expression responded to treatment with 1000nM T4 with enhanced migration as compared with untreated cells (P=0.02). Conclusions: Increased thyroid cancer cells migration in response to supraphysiologic levels of T4 may suggest enhanced metastatic potential. Future directions involve using in vitro 3D models and in vivo mouse models to study the effect of THs on TC progression.
Presentation: Saturday, July 12, 2025