Abstract 4766: Follicle stimulating hormone (FSH) inhibits apoptosis in ovarian cancer cell through regulating OCT4 stem cell signal pathway.

Abstract

Abstract Ovarian cancer is the most lethal malignancy of the female reproductive system with an overall mortality rate of greater than 70%. Our group has demonstrated that Follicle stimulating hormone (FSH) stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis, and facilitates neovascularization by increasing expression of vascular endothelial growth factor (VEGF). OCT4, a stem cell marker, is overexpressed in several types of human cancer and can induce resistance to chemotherapy and inhibition of apoptosis. We have found that FSH stimulates the expression of OCT4 mRNA and protein in a time- and dose-dependent manner. Subcellular analysis by immunofluorescent staining confirmed that FSH stimulation increased OCT4 protein expression in both the cytoplasm and nucleus of ovarian cancer cells. Re-expression of OCT4 in ovarian cancer cells reversed the inhibition of apoptosis induced by FSH, whereas siRNA-mediated knockdown of OCT4 resulted in a significantly rate of apoptosis. Depletion of OCT4 resulted in reduction of p-AKT and survivin, and also blocked FSH-induced upregulation of p-AKT and survivin. Moreover, FSH stimulation induced the expansion of CD44+CD117+ cells with a stem cell-like phenotype. Interestingly, re-expression of OCT4 enhanced the expression of Notch, Sox2, and Nanog, molecules that play critical roles in cancer stem cell proliferation and differentiation. FSH upregulated the expression of Notch, Sox2 and Nanog and these effects were abolished by knocking down OCT4, suggesting that several cancer stem cell pathways are involved in FSH regulation. We have also examined OCT4 expression in surgical specimens of ovarian cancer. Immunohistostaining revealed that OCT4 expression was increased in ovarian carcinoma compared with benign cystadenomas and borderline tumors, and OCT4 expression was significantly correlated with histological grade. Staining for OCT4 was increased in serous cystadenocarcinoma, when compared with clear cell carcinoma. In summary, the OCT4 cancer stem cell signaling pathway may mediate FSH-induced inhibition of apoptosis and could provide a target for treatment of ovarian cancer. Citation Format: Zhenbo Zhang, Yaping Zhu, Xianming Xu, Xiaowei Xi, Robert C. Bast, Yinhua Yu, Youji Feng. Follicle stimulating hormone (FSH) inhibits apoptosis in ovarian cancer cell through regulating OCT4 stem cell signal pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2013-4766