The Interplay Between Epithelial-Mesenchymal Transition (EMT) and the Thyroid Hormones-αvβ3 Axis in Ovarian Cancer

Ovarian cancer is a highly metastatic disease. The metastatic potential is enhanced by epithelial to mesenchymal transition (EMT) in which alpha v beta 3 integrin plays a role. Thyroid hormones (l-thyroxine, T4, and 3,5,3'-triiodo-l-thyronine, T3) bind this integrin, and we hypothesized that the thyroid hormone-alpha v beta 3 axis may be involved in EMT activity in ovarian cancer. The transcription (mRNA), protein abundance (westerns), and protein localization (fluorescence microscopy) of several EMT markers were studied in ovarian cancer cells (OVCAR-3, A2780, and SKOV-3) treated with 1 nM T3 or 100 nM T4 for 1-24 h. The protein levels of beta-catenin, and its downstream targets, zeb-1, slug, and vimentin, were significantly induced by both hormones, while the effect on transcription was limited. The pre-incubation of the cells overnight with two integrin inhibitors, RGD (0.1-10 mu M) or alpha v beta 3 blocking antibody (1-100 ng/mL), prevented the induction of beta-catenin by T3 and zeb-1 by T4, indicating direct integrin involvement. The transcription of the mesenchymal markers, beta-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, was inhibited. Our results suggest a novel role for the thyroid hormone-alpha v beta 3 axis in EMT, with possible implications for ovarian cancer metastasis.