Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor a (ERa). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERa antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERa phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERa was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERa and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERa promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.
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Hsieh, M. T., Wang, L. M., Changou, C. A., Chin, Y. T., Yang, Y. C. S. H., Lai, H. Y., Lee, S. Y., Yang, Y. N., Whang-Peng, J., Liu, L. F., Lin, H. Y., Mousa, S. A., & Davis, P. J. (2017). Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells. Oncotarget, 8(15), 24237-24249. https://doi.org/10.18632/oncotarget.10757