Pigment epithelium-derived factor is estrogen sensitive and inhibits the growth of human ovarian cancer and ovarian surface epithelial cells

被引:83
作者
Cheung, Lydia W. T.
Au, Simon C. L.
Cheung, Annie N. Y.
Ngan, Hextan Y. S.
Tombran-Tink, Joyce
Auersperg, Nelly
Wong, Alice S. T.
机构
[1] Univ Hong Kong, Dept Zool, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[3] Univ Hong Kong, Dept Obstet & Gynecol, Hong Kong, Hong Kong, Peoples R China
[4] Univ Missouri, Div Pharmaceut Sci, Kansas City, MO 64110 USA
[5] Chinese Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
[6] Yale Univ, Sch Med, Dept Ophthalmol, New Haven, CT 06520 USA
[7] Univ British Columbia, Dept Obstet & Gynecol, Vancouver, BC V6H 3V5, Canada
关键词
D O I
10.1210/en.2006-0168
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (E-2) 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 E-2. E-2 promoted OSE and ovarian cancer cell growth, whereas simultaneous treatment with E-2 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 maye of relevance in carcinogenesis.
引用
收藏
页码:4179 / 4191
页数:13
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