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Nm23-H1 Suppresses Tumor Cell Motility by Down-regulating the Lysophosphatidic Acid Receptor EDG2

¹ Women's Cancers Section, Laboratory of Molecular Pharmacology; ² Clinical Molecular Profiling Core, Genetics Branch; and ³ Extracellular Matrix Pathology Section, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; ⁴ INSERM U680, Université Pierre et Marie Curie-Paris6, Faculté de Médicine, UMRS680, Paris, France; and ⁵ Biologie de Différenciation et du Développement, Université Victor Segalen-Bordeaux2, Bordeaux, France

Requests for reprints: Christine E. Horak, Women's Cancer Section, Laboratory of Molecular Pharmacology, National Cancer Institute/NIH, 37 Convent Drive, Bethesda, MD 20892. Phone: 301-594-0706; Fax: 301-402-8910; E-mail: horakc{at}mail.nih.gov.

Exogenous overexpression of the metastasis suppressor gene Nm23-H1 reduces the metastatic potential of multiple types of cancer cells and suppresses in vitro tumor cell motility and invasion. Mutational analysis of Nm23-H1 revealed that substitution mutants P96S and S120G did not inhibit motility and invasion. To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. Reduced expression of these genes coincident with elevated Nm23-H1 expression was observed in human breast tumor cohorts, a panel of breast carcinoma cell lines, and hepatocellular carcinomas from control versus Nm23-M1 knockout mice. The functional significance of the down-regulated genes was assessed by transfection and in vitro motility assays. Only EDG2 overexpression significantly restored motility to Nm23-H1–suppressed cancer cells, enhancing motility by 60-fold in these cells. In addition, silencing EDG2 expression with small interfering RNA reduced the motile phenotype of metastatic breast cancer cells. These data suggest that Nm23-H1 suppresses metastasis, at least in part, through down-regulation of EDG2 expression. [Cancer Res 2007;67(15):7238–46]

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