Journal
ONCOTARGET
Volume 8, Issue 15, Pages 24237-24249Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10757
Keywords
thyroid hormone; integrin alpha v beta 3; ER alpha crosstalk; ovarian cancer
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Funding
- Wang-Fan Hospital, Taipei Medical University, Taipei, Taiwan [102TMU-WFH-11]
- Ministry of Science and Technology, Taiwan [MOST-102-2311-B-038-001, MOST103-2320-B-038-050, 104-2314-B-038 -046 -MY3]
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Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin alpha v beta 3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T-4) 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 (T-3) at a supraphysiologic concentration. Thyroid hormone (T-4 and T-3) 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 av or beta 3 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 (ER alpha). Confocal microscopy indicated that both T-4 and estradiol (E-2) caused nuclear translocation of integrin av and phosphorylation of ER alpha. The specific ER alpha antagonist (ICI 182,780; fulvestrant) blocked T-4-induced ERK1/2 activation, ER alpha phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin av and phosphorylated ER alpha was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T-4-and E2-induced nuclear co-localization of phosphorylated ER alpha and integrin av are dissimilar. Chromatin immunoprecipitation results showed that T-4-induced binding of integrin av monomer to ER alpha promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin av and ER alpha, mimicking functions of E-2.
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