Abstract
Estrogen signaling influences the development and progression of ovarian tumors, but the underlying mechanisms are not well understood. In a previous study we demonstrated that impairment of estrogen receptor alpha (ERα)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p. In this study we investigated the role of OLFM4 in ovarian serous adenocarcinoma. Ovarian serous adenocarcinoma tissues had reduced OLFM4 expression. Expression of OLFM4 was positively correlated with ERα expression, and estrogen (E2) treatment in ovarian cancer cells induced OLFM4 expression in an ERα-dependent manner. In contrast to ERα, miR-486-5p levels were inversely correlated with OLFM4 expression in ovarian serous adenocarcinoma. Ovarian cancer cells transfected with miR-486-5p mimics showed decreased OLFM4 mRNA expression, and ovarian cancer cells treated with E2 showed reduced cellular miR-486-5p levels. OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells. Low expression of OLFM4 was also associated with high tumor FIGO stage and poor tumor differentiation. These results suggest OLFM4 is downregulated by miR-486-5p, which contributes to ovarian cancer tumorigenesis. Conversely, estrogen receptor signaling downregulates miR-486-5p and upregulates OLFM4 expression, slowing the development and progression of ovarian cancer.
Highlights
Ovarian cancer, together with endometrial cancer and cervical carcinoma, are the three most common gynecological malignant tumors [1]
We sought to investigate the effects of olfactomedin 4 (OLFM4) on ovarian serous adenocarcinoma cells. small interfering RNA (siRNA) knockdown of OLFM4 promoted cell proliferation in both HO8910-pm and SKOV3 cells (Figure 2A), but had no effect on cell apoptosis (Figure 2D)
In a transwell migration assay, the mean number of invaded cells per one visual field was greater with OLFM4 knockdown compared with the control group (Figure 2C). These results suggest that OLFM4 regulates ovarian serous adenocarcinoma cell proliferation and migration
Summary
Together with endometrial cancer and cervical carcinoma, are the three most common gynecological malignant tumors [1]. Epitheliumderived ovarian serous tumors include benign serous cystadenoma, serous borderline tumors, and malignant serous adenocarcinoma. Ovarian serous cystadenomas are common ovarian lesions that may be precursors of serous borderline tumors, which can in turn progress to ovarian serous adenocarcinomas [2]. Ovarian serous adenocarcinoma accounts for about 75% of ovarian epithelial tumors and can be highly invasive. The ovaries secrete both estrogen and progesterone, and estrogens play a role in the development, growth, invasion and metastasis of ovarian tumors. Estrogen receptor alpha (ERα) induces gene expression changes in ovarian cancer cells [3]. High ERα expression is associated with reduced apoptosis in poorly-differentiated ovarian cancer [4]. The mechanisms of estrogens actions on the development and progression of gynecological tumors is not well understood
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