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 Mills, Napoleone Ferrara, Robert B. Jaffe

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Ovarian Neoplasms
Vascular Endothelial Growth Factor A
Epithelial Cells
Growth
Neoplasms
Lysophosphatidic Acid Receptors
lysophosphatidic acid
Cell Line
Messenger RNA
Simian virus 40
Ovulation Induction
Ascitic Fluid
Viral Tumor Antigens
Ascites
Transcriptional Activation
Transfection
Half-Life
Transcription Factors
Binding Sites

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hu, Y. L., Tee, M. K., Goetzl, E. J., Auersperg, N., Mills, G., 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.

Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. / Hu, Yu Long; Tee, Meng Kian; Goetzl, Edward J.; Auersperg, Nelly; Mills, Gordon; Ferrara, Napoleone; Jaffe, Robert B.

In: Journal of the National Cancer Institute, Vol. 93, No. 10, 16.05.2001, p. 762-768.

Research output: Contribution to journalArticle

Hu, YL, Tee, MK, Goetzl, EJ, Auersperg, N, Mills, G, Ferrara, N & Jaffe, RB 2001, 'Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells', Journal of the National Cancer Institute, vol. 93, no. 10, pp. 762-768.
Hu, Yu Long ; Tee, Meng Kian ; Goetzl, Edward J. ; Auersperg, Nelly ; Mills, Gordon ; Ferrara, Napoleone ; Jaffe, Robert B. / Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. In: Journal of the National Cancer Institute. 2001 ; Vol. 93, No. 10. pp. 762-768.
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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.",
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AU - Hu, Yu Long

AU - Tee, Meng Kian

AU - Goetzl, Edward J.

AU - Auersperg, Nelly

AU - Mills, Gordon

AU - Ferrara, Napoleone

AU - Jaffe, Robert B.

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N2 - 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.

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