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Lysophosphatidic Acid Is a Major Regulator of Growth-Regulated Oncogene in Ovarian Cancer

¹ Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia and Departments of ² Molecular Therapeutics, ³ Gynecological Oncology, and ⁴ Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xianjun Fang, Department of Biochemistry, Virginia Commonwealth University, PO Box 980614, Richmond, VA 23298. Phone: 804-828-0787; Fax: 804-828-1473; E-mail: xfang{at}vcu.edu.

Growth-regulated oncogene (GRO), a member of the chemokine superfamily, is commonly expressed in transformed cells and contributes to angiogenesis and tumorigenesis. Here, we report that increased GRO levels are detected in the plasma and ascites of ovarian cancer patients. Ovarian cancer cell lines in culture express and secrete GRO. However, when they are starved in serum-free medium, ovarian cancer cells ceased producing GRO, suggesting that GRO is not constitutively expressed but rather is produced in response to exogenous growth factors in ovarian cancer cells. The prototype peptide growth factors present in serum such as platelet-derived growth factor, insulin-like growth factor I, and insulin do not stimulate GRO production by ovarian cancer cells. In contrast, lysophosphatidic acid (LPA), a glycerol backbone phospholipid mediator present in serum and ascites of ovarian cancer patients, is a potent inducer of GRO expression in ovarian cancer cell lines. Treatment of ovarian cancer cells with LPA leads to transcriptional activation of the GRO gene promoter and robust accumulation of GRO protein in culture supernatants. The action of LPA on GRO expression is mediated by LPA receptors, particularly the LPA₂ receptor in that ectopic expression of these receptors restores the LPA-dependent GRO production in nonresponsive cells. Down-regulation of LPA₂ expression by small interfering RNA (siRNA) in ovarian cancer cells desensitizes GRO production in response to LPA. The effect of serum on GRO production is also significantly decreased by siRNA inhibition of LPA₂ expression. These studies identify LPA as a primary regulator of GRO expression in ovarian cancer. (Cancer Res 2006; 66(5): 2740-8)

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