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Pigment Epithelium-Derived Factor Is Estrogen Sensitive and Inhibits the Growth of Human Ovarian Cancer and Ovarian Surface Epithelial Cells

Departments of Zoology (L.W.T.C., A.S.T.W.), Pathology (A.N.Y.C.), and Obstetrics and Gynecology (H.Y.S.N.), University of Hong Kong, Hong Kong; Department of Physiology (S.C.L.A.), Chinese University of Hong Kong, Hong Kong; Division of Pharmaceutical Sciences (J.T.-T.), University of Missouri, Kansas City, Missouri 64110; Department of Ophthalmology (J.T.-T.), Yale University School of Medicine, New Haven, Connecticut 06520; and Department of Obstetrics and Gynecology (N.A.), University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

Address all correspondence and requests for reprints to: Alice S. T. Wong, University of Hong Kong, Department of Zoology, 4S-14 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong. E-mail: awong1{at}hku.hk.

Epithelial ovarian carcinoma is the most lethal gynecological cancer. However, little is known about the molecular mechanisms underlying the disease development and progression. In this study, we found that the expression of pigment epithelium-derived factor (PEDF) was greatly reduced in ovarian tumors and in ovarian cancer cell lines when compared with their normal precursor, ovarian surface epithelium (OSE). In addition, we showed that exogenous PEDF inhibited the growth of cultured human OSE as well as ovarian cancer cell lines, whereas targeted inhibition of endogenous PEDF using small interfering RNA or neutralizing PEDF antibody promoted the growth of these cells, confirming that the growth-inhibitory effect was PEDF specific. We also report for the first time that estrogen is an important upstream regulator of PEDF in human OSE. Treatment of the cultured cells with 17ß-estradiol (E₂) inhibited the expression of PEDF protein and mRNA in a dose- and time-dependent manner, which could be reversed by the specific estrogen receptor antagonist, ICI 182,780, indicating that the regulation was estrogen receptor-mediated. We further showed that this down-regulation of PEDF gene transcription was a direct, primary effect of E₂. E₂ promoted OSE and ovarian cancer cell growth, whereas simultaneous treatment with E₂ and PEDF abrogated the estrogenic growth stimulation of these cells. This study is the first to demonstrate a role of PEDF in OSE biology and ovarian cancer and suggests that the loss of PEDF may e of relevance in carcinogenesis.