Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells

Yu Long Hu, Meng Kian Tee, Edward J. Goetzl, Nelly Auersperg, Gordon B. Mills, Napoleone Ferrara, Robert B. Jaffe

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    212 Scopus citations

    Abstract

    Background: Lysophosphatidic acid (LPA) stimulates ovarian tumor growth at concentrations present in ascitic fluid. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and plays a pivotal role in the formation of ovarian cancer-associated ascites. We examined whether LPA promotes ovarian tumor growth by increasing angiogenesis via VEGF. Methods: VEGF expression was examined in a simian virus 40 T-antigen-immortalized ovarian surface epithelial cell line (IOSE-29) and in ovarian cancer cell lines (OVCAR-3, SKOV-3, and CAOV-3) treated with LPA. VEGF promoter activity was measured in OVCAR-3 cells after transfection or cotransfection with c-Fos and c-Jun, components of AP1 transcription factor, potential binding sites for which are present in the VEGF promoter. The expression of the LPA receptors Edg2 and Edg4 was also assessed. All statistical tests were two-sided. Results: LPA treatment increased steady-state VEGF messenger RNA (mRNA) levels in OVCAR-3 cells in a time- and dose-dependent fashion and stimulated VEGF promoter activity without prolonging mRNA half-life in these cells, but LPA had little effect on IOSE-29 cells. Forced overexpression of c-Jun and c-Fos in OVCAR-3 cells stimulated VEGF promoter activity fourfold. LPA also elevated VEGF protein levels by 1.5-fold in SKOV-3 cells (P = .0148), 1.9-fold in CAOV-3 cells (P<.001), and threefold in OVCAR-3 cells (P<.0001). Both Edg2 and Edg4 were detected in ovarian cancer cells; however, only Edg2 was present in normal ovarian surface epithelial cells and IOSE-29 cells. Conclusions: LPA stimulates ovarian tumor growth, at least in part, via induction of VEGF expression through transcriptional activation. However, this LPA response is not evident in normal ovarian surface epithelial cells. Our data suggest that Edg4, but not Edg2, plays a role in LPA stimulation of ovarian tumor growth.

    Original languageEnglish (US)
    Pages (from-to)762-768
    Number of pages7
    JournalJournal of the National Cancer Institute
    Volume93
    Issue number10
    StatePublished - May 16 2001

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Hu, Y. L., Tee, M. K., Goetzl, E. J., Auersperg, N., Mills, G. B., Ferrara, N., & Jaffe, R. B. (2001). Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. Journal of the National Cancer Institute, 93(10), 762-768.