Abstract
Follicle-stimulating hormone (FSH) is closely related to the pathogenesis and progression of epithelial ovarian cancer (EOC). However, until now, knowledge relating to FSH-driven signalling pathways that lead to the growth of EOC remained incomplete. We sought to explore whether sphingosine kinase (SphK) could mediate FSH-induced ovarian cancer cell proliferation and which pathway might be involved in this process. The expression of phospho-SphK1 and phospho-SphK2 was detected in sections of EOC tissues by Immunohistochemical staining, and clinical significances were analyzed by statistical analysis. EOC cells were treated with FSH or/and SKI-II. CCK8 assays and colony formation assays were used to investigate cell proliferation. Western blot was carried out to detect protein expression in EOC cell line after treated with FSH. Here, for the first time, we provide evidence that high expression levels of phospho-SphK1 and phospho-SphK2 were both prognostic indicators of overall survival (OS) in EOC. Additionally, the expression levels of both phospho-SphK1 and phospho-SphK2 were closely correlated with the expression level of follicle-stimulating hormone receptor (FSHR) in ovarian cancer tissues. FSH stimulated the phosphorylation of both SphK1 and SphK2 and was able to regulate the survival and growth of ovarian cancer cells by activating SphK1 and SphK2 through ERK1/2. Both isoenzymes of SphK were equally responsible for FSH-induced cell proliferation of EOC. Both Erk1/2 and Akt activation play important roles in mediating FSH-induced cell proliferation after phosphorylation of SphK. Moreover, our data demonstrated that S1P receptor 1 (S1PR1) and S1PR3, key components of the SphK signalling system, were involved in FSH-mediated proliferation of EOC. Taken together, the results of the current study revealed that SphK is an essential mediator in FSH-induced proliferation of ovarian cancer cells in EOC, which indicates a new signalling pathway that controls FSH-mediated growth in EOC and suggests a new strategy that pharmaceutically targets both isoenzymes of SphK for the management of ovarian cancer.
Highlights
Follicle-stimulating hormone (FSH) is closely related to the pathogenesis and progression of epithelial ovarian cancer (EOC)
We examined the relationship between phospho-SphK1/phospho-SphK2 expression levels in EOC and clinicopathological characteristics (Table 1)
We found that both phospho-SphK1 and phospho-SphK2 were significantly correlated with the follicle-stimulating hormone receptor (FSHR) level in tumour tissue (Fig. 1B)
Summary
Follicle-stimulating hormone (FSH) is closely related to the pathogenesis and progression of epithelial ovarian cancer (EOC). FSH stimulated the phosphorylation of both SphK1 and SphK2 and was able to regulate the survival and growth of ovarian cancer cells by activating SphK1 and SphK2 through ERK1/2 Both isoenzymes of SphK were responsible for FSH-induced cell proliferation of EOC. Previous studies showed that 80–90% of ovarian cancers originate from the ovarian surface epithelium, and multiple reports have confirmed the involvement of endocrine factors in the tumorigenesis of epithelial ovarian cancer (EOC) In both epidemiological and clinical studies, increasing evidence has indicated a strong association between high levels of FSH and an increased incidence of EOC2–5. Whether FSHinduced activation of the Erk pathway in ovarian cancer cells causes variation in SphK1 and SphK2 expression and activity is still unclear
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