Pigment epithelium-derived factor is estrogen sensitive and inhibits the growth of human ovarian cancer and ovarian surface epithelial cells.
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 17 beta-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.
Cheung
Lydia W T
LW
Department of Zoology, University of Hong Kong, 4S-14 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong.
Au
Simon C L
SC
Cheung
Annie N Y
AN
Ngan
Hextan Y S
HY
Tombran-Tink
Joyce
J
Auersperg
Nelly
N
Wong
Alice S T
AS
D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010053:Ovary / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000494:pharmacology*; D000099174:Pigment Epithelium-Derived Factor
D000906:Antibodies; D004958:Estradiol; D005136:Eye Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor