Research Papers:

Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells

Meng-Ti Hsieh, Le-Ming Wang, Chun A. Changou, Yu-Tang Chin, Yu-Chen S.H. Yang, Hsuan-Yu Lai, Sheng-Yang Lee, Yung-Ning Yang, Jacqueline Whang-Peng, Leroy F. Liu, Hung-Yun Lin _, Shaker A. Mousa and Paul J. Davis

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Oncotarget. 2017; 8:24237-24249. https://doi.org/10.18632/oncotarget.10757

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Meng-Ti Hsieh1,2,*, Le-Ming Wang3,*, Chun A. Changou2,4,5, Yu-Tang Chin1,6,7,8, Yu-Chen S.H. Yang9, Hsuan-Yu Lai1, Sheng-Yang Lee6,7,8, Yung-Ning Yang10, Jacqueline Whang-Peng1, Leroy F. Liu1, Hung-Yun Lin1,2, Shaker A. Mousa11, Paul J. Davis11,12

1Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

2The PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

3Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

4Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan

5Core Facility, Taipei Medical University, Taipei, Taiwan

6Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan

7School of Dentistry, Taipei Medical University, Taipei, Taiwan

8Center for Teeth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan

9Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan

10Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan

11Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA

12Department of Medicine, Albany Medical College, Albany, New York, USA

*These authors contributed equally to this work

Correspondence to:

Yung-Ning Yang, email: ancaly@yahoo.com.tw

Hung-Yun Lin, email: linhy@tmu.edu.tw

Keywords: thyroid hormone, integrin αvβ3, ERα crosstalk, ovarian cancer

Received: April 23, 2016     Accepted: July 10, 2016     Published: July 21, 2016


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 α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα 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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