Nm23-H1 suppresses tumor cell motility by down-regulating the lysophosphatidic acid receptor EDG2.

Abstract

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.

• Authors: Christine E Horak, Jong Heun Lee, Abdel G Elkahloun, Mathieu Boissan, Sylvie Dumont, Tara K Maga, Sandrine Arnaud-Dabernat, Diane Palmieri, William G Stetler-Stevenson, Marie-Lise Lacombe, Paul S Meltzer, Patricia S Steeg
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 15 Pg. 7238-46 (Aug 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17671192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Laminin
• NM23 Nucleoside Diphosphate Kinases
• Proteoglycans
• RNA, Messenger
• Receptors, Lysophosphatidic Acid
• matrigel
• Collagen
• NME1 protein, human
• Nme1 protein, mouse
• Nucleoside-Diphosphate Kinase

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Movement
• Cohort Studies
• Collagen (metabolism)
• Down-Regulation
• Drug Combinations
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (physiology)
• Gene Silencing
• Humans
• Immunoblotting
• Immunoenzyme Techniques
• Laminin (metabolism)
• Mice
• Mice, Knockout
• NM23 Nucleoside Diphosphate Kinases
• Nucleoside-Diphosphate Kinase (physiology)
• Oligonucleotide Array Sequence Analysis
• Proteoglycans (metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Lysophosphatidic Acid (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured