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Gynecol Oncol. 2004 Nov;95(2):314-22.

Lysophosphatidic acid enhances epithelial ovarian carcinoma invasion through the increased expression of interleukin-8.

Author information

1
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, New York University School of Medicine, New York, NY 10016, USA.

Abstract

OBJECTIVE:

We previously reported that lysophosphatidic acid (LPA) stimulates cellular invasion of ovarian cancer (OVCA) cells by enhancing membrane-type-1-matrix metalloproteinase (MT1-MMP)-mediated activation of MMP2. Here, we investigate a second mechanism in which LPA enhances cellular invasion through the increased expression of IL-8, independent of the expression or activation of MMP2.

METHODS:

Epithelial ovarian carcinoma cells (DOV 13) were exposed to LPA (80 microM) and IL-8 (100 ng/ml) for 24 h. IL-8 expression was quantified by enzyme-linked immunosorbent assay (ELISA). Cellular invasion (Matrigel invasion), migration (colloidal gold), and urinary-type plasminogen activator (uPA) activity (colorimetric assay) were quantified. Conditioned medium was also assayed for MMP activation and expression by SDS-PAGE gelatin zymography, ELISA, and Western blotting. In addition, IL-8 neutralizing antibody and MMP inhibitors were employed.

RESULTS:

Our results found LPA to increase IL-8 expression threefold. IL-8 did not affect cellular migration, MMP2 activation, or uPA expression. However, exposure to various concentrations of IL-8 increased cellular invasiveness. Using an IL-8 blocking antibody and various MMP inhibitors, we determined that the increase in invasion was IL-8-dependent, while independent of the activation of MMP2 or MMP9. We further determined IL-8 exposure increased the expression of matrilysin (MMP7). Cells exposed to LPA and IL-8 resulted in a synergistic effect on cellular invasion. Adding the IL-8 blocking antibody, slightly decreased cellular invasion, indicating LPA in part, increases cellular invasion through the increased expression of IL-8.

CONCLUSION:

We have identified a separate mechanism of enhanced cellular invasion, which is independent of MMP2 activation and involves the increased expression of IL-8 and subsequent increased expression of MMP7.

PMID:
15491751
DOI:
10.1016/j.ygyno.2004.08.001
[Indexed for MEDLINE]

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