Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway.
Gonadotropin signaling plays an indispensable role in ovarian cancer progression. We previously have demonstrated that thyrostimulin and thyroid-stimulating hormone receptor (TSHR), the most ancient glycoprotein hormone and receptor pair that evolved much earlier than the gonadotropin systems, co-exist in the ovary. However, whether thyrostimulin-driven TSHR activation contributes to ovarian cancer progression in a similar way to gonadotropin receptors has never been explored. In this study, we first found that TSHR is expressed in both rat normal ovarian surface epithelium and human epithelial ovarian cancers (EOCs). Using human NIH:OVCAR-3 as a cell model, we demonstrated that thyrostimulin promotes EOC cell proliferation as strongly as gonadotropins. Thyrostimulin treatment not only activated adenylyl cyclase and the subsequent PKA, MEK-ERK1/2 and PI3K-AKT signal cascades, but also trans-activated EGFR signaling. Signaling dissection using diverse inhibitors indicated that EOC cell proliferation driven by thyrostimulin-TSHR signaling is PKA independent, but does require the involvement of the MEK-ERK and PI3K-AKT signal cascades, which are activated mainly via the trans-activation of EGFR. Thus, not only have we proved that this ancient glycoprotein hormone system is involved in NIH:OVCAR-3 cell proliferation for the first time, but also that it may possibly become a novel oncotarget when studying ovarian cancer.
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Wei-Lin
WL
Huang
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Zhongyou
Z
Li
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Ting-Yu
TY
Lin
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Sheng-Wen
SW
Wang
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Fang-Ju
FJ
Wu
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Ching-Wei
CW
Luo
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011989:Receptors, Thyrotropin / Q000378:metabolism*; D015398:Signal Transduction
D006023:Glycoproteins; D011989:Receptors, Thyrotropin; C458339:thyrostimulin; D066246:ErbB Receptors