Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway

Abstract

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.

Long noncoding RNA NBAT-1 suppresses tumorigenesis and predicts favorable prognosis in ovarian cancer

“…Consistent with functional characterization in vitro, the overexpression of NBAT-1 leads to signifcantly metastasis-related factors (MMP-2 and MMP-9) downregulated both in OVCAR-3 and TOV112D cell lines compared to the empty vector group (Figure 4A and B). As reported previously, the ERK1/2 and AKT signal pathways are usually activated in OC 14,15. As in previously published articles, our study showed that p-ERK1/2 and p-AKT protein expressions were reduced in the pcDNA-NBAT-1 group compared to the empty vector group in both TOV112D and OVCAR-3 cell lines.…”

The Role of Endocrine G Protein-Coupled Receptors in Ovarian Cancer Progression

“…However, recent evidence suggests that TSHR is highly expressed in ovarian cancer tumors (60). Patients with high tumor TSHR expression levels had lower survival rates compared to patients with low TSHR tumor expression levels (61).…”

The role of thyrostimulin and its potential clinical significance

“…Th e human ovarian carcinoma cell line NIH:OVCAR-3 expresses both GPA2 and GPB5 suggesting that these cells also express thyrostimulin (Huang et al 2016). NIH:OVCAR-3 expresses functional TSHR, which is also present in mammalian OSE (Sun et al 2010).…”

“…Th is is noteworthy as EGFR is linked with the progression of ovarian cancer (Glaysher et al 2013). Moreover, an EGFR inhibitor partially inhibits thyrostimulin-induced ERK phosphorylation and completely inhibits thyrostimulininduced AKT activation (Huang et al 2016). Both of these pathways regulate epithelial ovarian cancer proliferation, further highlighting the potential role of thyrostimulin in the progression of ovarian cancer (Chan et al 2012;Cheaib et al 2015).…”

“…In addition, thyrostimulin reduces the expression of proto-oncogene c-Kit (Huang et al 2016). Loss of c-Kit has been linked to breast cancer and a poor prognosis in ovarian cancer (Tonary et al 2000;Tsutsui et al 2006).…”