Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C.
The risk and severity of ovarian carcinoma, the leading cause of gynecologic malignancy death, are significantly elevated in postmenopausal women. Ovarian failure at menopause, associated with a reduction in estrogen secretion, results in an increase of the gonadotropic luteinizing hormone (LH) and follicle-stimulating hormone (FSH), suggesting a role for these hormones in facilitating the progression of ovarian carcinoma. The current study examined the influence of hormonal stimulation on lymphangiogenesis in ovarian cancer cells. In vitro stimulation of ES2 ovarian carcinoma cells with LH and FSH induced expression of vascular endothelial growth factor (VEGF)-C. In vivo, ovariectomy of mice resulted in activation of the VEGF-C promoter in ovarian carcinoma xenografts, increased VEGF-C mRNA level, and enhanced tumor lymphangiogenesis and angiogenesis. Seeking the molecular mechanism, we examined the role of lens epithelium-derived growth factor (LEDGF/p75) and the possible contribution of its putative target, a conserved stress-response element identified in silico in the VEGF-C promoter. Using chromatin immunoprecipitation, we showed that LEDGF/p75 indeed binds the VEGF-C promoter, and binding is augmented by FSH. A corresponding hormonally regulated increase in the LEDGF/p75 mRNA and protein levels was observed. Suppression of LEDGF/p75 expression using small interfering RNA, suppression of LH and FSH production using the gonadotropin-releasing hormone antagonist cetrorelix, or mutation of the conserved stress-response element suppressed the hormonally induced expression of VEGF-C. Overall, our data suggest a possible role for elevated gonadotropins in augmenting ovarian tumor lymphangiogenesis in postmenopausal women.
Sapoznik
Stav
S
Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.
Cohen
Batya
B
Tzuman
Yael
Y
Meir
Gila
G
Ben-Dor
Shifra
S
Harmelin
Alon
A
Neeman
Michal
M
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology*; D042601:Lymphatic Vessels / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C504649:PSIP1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone