Follicle-stimulating Hormone (FSH) Enhances The Proliferation Of Ovarian Epithelial Cancer Cells Through Activating Transient Receptor Potential Channel C3(TRPC3)

At present, ovarian epithelial cancer is the leading killer among all gynecological malignancies. Despite much research, development of ovarian epithelial cancer is still not fully understood. The five-year survival rate for this disease still remains about30%.Recent studies suggest that Follicle-stimulating hormone (FSH) may play a major role in ovarian epithelial carcinogenesis. Our group has demonstrated that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibit apoptosis, and facilitate neovascularization by increasing vascular endothelial growth factor (VEGF) expression. To understand the mechanisms of FSH stimulation, we have performed gene expression arrays and confirmed by Western blots. Interestingly, we found that the effects of FSH tightly related to the transient receptor potential channel C3(TRPC3). FSH increases the expression of TRPC3at both mRNA and protein levels; inhibition of TRPC3expression by siRNA impaired the biological activities of FSH on ovarian cancer cell lines, such as proliferation, cell cycle promotion and anti-apoptotic effects. The TRPC channels are nonselective cation channels with permeability to Ca2+. Increases in cytosolic free Ca2+can result in different physiological changes including cell growth, differentiation and death. TRPC3is one of7TRPC family members. Our previous works have shown that TRPC3contributes to the progression of human ovarian cancer. The TRPC3protein levels in human ovarian cancer specimens were greatly increased than those in normal ovarian specimens. Downregulating TRPC3expression led to reduction of proliferation, suppression in epidermal growth factor-induced Ca2+influx, and suppressed the xenograft tumor formation. In this study, we further explored the interaction of FSH-TRPC3. FSH stimulation could translocate TRPC3from cytoplasm to cell membrane in addition to increasing the quantity of the TRPC3protein, which facilitated the influx of Ca2+via TRPC3specific agonist. Signal transduction investigation indicated that knocking down of TRPC3abrogated Akt/PKB phosphorylation by FSH stimulation, leading to the decreases of down-stream signal molecules, such as survivin, HIFla, VEGF. My results indicated that TRPC3is a significant molecule enrolled in the tumor-stimulant activity of FSH; it could be a potential therapeutic target of ovarian cancer. We futher explored the role of TRPC3in the prognosis of ovarian cancers. The expression of TRPC3on the OEC tissue sections weree examined by immunohistochemistry and the relation between other clinicopathological parameters was analysed. When using expression score method to calculate and devide the intesity of TRPC3exression into high and low levels, it indicated that the expression intensity of TRPC3was varied between different types of OEC, between different tissue differentiation levels of serous adenocarcinoma. Cox regression analysis of the relationship between free disease survival (FDS) intervals and clinicopathological parameters showed that TRPC3expression as well as pathological type and clinical phase were meaningful indicators of prognosis, as patients with high expressed TRPC3tended to recur earlier than those with low expression level (relative risk=2.86).Further understanding the interaction of FSH-TRPC3in the process of ovarian carcinogenesis and development will ultimately help developing an effective cancer prevention method and find a novel targeted therapy for ovarian cancer.