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. 2009 Dec 15;69(24):9306-14.
doi: 10.1158/0008-5472.CAN-09-1213.

Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C

Stav Sapoznik  1 , Batya Cohen, Yael Tzuman, Gila Meir, Shifra Ben-Dor, Alon Harmelin, Michal Neeman
Affiliations

Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C (VSports)

Stav Sapoznik et al. Cancer Res. .

Abstract

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. VSports手机版.

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Figures

Figure 1
Figure 1. Hormonal stimulation induces VEGF-C elevation in vitro
A. ChIP carried out on hormonally stimulated or control ES2 cells using anti LEDGF/p75 antibody and primers specific for the VEGF-C promoter area (upper panel), or GAPDH for input samples (lower panel). IgG antibody was used as a negative control. B. Real time PCR using VEGF-C specific primers (left) or LEDGF/p75 specific primers (right) carried out on RNA derived from ES2 hormonally stimulated cells. (n=3) C. Western blot analysis using anti VEGF-C, anti LEDGF/p75 or β-tubulin antibodies carried out on total cell lysate derived from ES2 hormonally stimulated cells. (n=3) D. Densitometric analysis of C.
Figure 2
Figure 2. Ovariectomy induces VEGF-C promoter activation in ovarian tumors
A. Time lapse bioluminescence imaging of ovariectomized (OVX) and control (−) mice subcutaneously injected with ES2 cells which stably express the firefly luciferase gene under VEGF-C promoter regulation. B. Total flux of photons derived from the tumor area of OVX and control mice subcutaneously injected with ES2 cells, which stably express the firefly luciferase gene under VEGF-C promoter regulation. C. Volume of tumors induced in OVX and control mice. (OVX n=5, control n=5).
Figure 3
Figure 3. GnRH blockade prevents the VEGF-C promoter enhanced activation in ovariectomized mice
A. Bioluminescence imaging of ovariectomized (OVX) and control tumor bearing mice either treated or untreated with cetrorelix. Mice were imaged 7 days following tumor induction. B. Total flux of photons derived from the tumor area of OVX and control tumor bearing mice, either treated or untreated with cetrorelix. (OVX n=5, OVX+cetrorelix n=5, control n=4, control+cetrorelix n=4).
Figure 4
Figure 4. Ovariectomy induces an elevation in VEGF-C and LEDGF/p75 mRNA levels in tumors
A. Real time PCR using VEGF-C specific primers carried out on RNA extracted from tumors. Data are presented as fold induction compared to control group. (OVX: n=4, Control: n=4, OVX + cetrorelix: n=5, Control + cetrorelix: n=3). B. Real time PCR using LEDGF/p75 specific primers carried out on RNA extracted from tumors. Data are presented as fold induction compared to control group (OVX: n=4, Control: n=4, OVX + cetrorelix: n=5, Control + cetrorelix: n=3). C. In situ hybridization using a VEGF-C specific probe of histological sections derived from tumors induced in OVX and control mice (OVX n=5, control n=5). D. In situ hybridization using a LEDGF/p75 specific probe of histological sections derived from tumors induced in OVX and control mice (OVX n=5, control n=5).
Figure 5
Figure 5. Ovariectomy induces lymphangiogenesis and angiogenesis in ovarian tumors
A. Immunohistochemical staining using anti LYVE-1 antibody of histological sections derived from tumors (upper panel) or the skin area in the vicinity of the tumors (lower panel) induced in OVX and control mice (OVX n=5, control n=5). Analysis of the data was carried out by calculating the percentage of fluorescent staining coverage in each field of view. B. Immunohistochemical staining using anti CD34 antibody of histological sections derived from tumors (upper panel) or the skin area in the vicinity of the tumors (lower panel) induced in OVX and control mice (OVX n=5, control n=5). Analysis of the data was carried out by calculating the percentage of fluorescent staining coverage in each field of view. C. Immunohistochemical staining using anti LYVE-1 antibody (upper panel) or anti Prox-1 antibody (lower panel) of histological sections derived from OVX and control mice.
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