Mitogenic effect of estrogen in human ovarian surface epithelial cells (OSE) involves downregulation of pigment epithelium-derived factor (PEDF)

Abstract

Objectives: To characterize the regulation of PEDF expression in OSE and its role in estrogen-dependent development of ovarian cancer derived from OSE. Methods: PEDF expression was examined in OSE cell lines and ovarian tumor tissues using immunohistochemistry, real-time PCR and Western blot. Cell proliferation and apoptosis were determined by MTT assay, TUNEL and Hoechst staining. Results: PEDF immunoreactivity was lower in a majority of ovarian tumors when compared with normal tissues. In cultured human OSE, exogenous PEDF caused significant growth inhibition and apoptosis. In line with the estrogen dependency of OSE-derived ovarian tumors, we showed for the first time that estrogen-induced OSE proliferation was accompanied by a specific inhibition of PEDF expression, which could be reversed by an estrogen receptor antagonist (ICI 182,780). Addition of exogenous PEDF antagonized the growth stimulatory effect of E2 on these cells, suggesting a negative role of PEDF in estrogen-induced OSE cell proliferation. Conclusion: This study is the first to identify PEDF as an ER-regulated target gene, and apart from its known function as a potent anti-angiogenic factor, is also implicated as a suppressor of estrogen-dependent ovarian tumor growth.