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Macrophage Migration Inhibitory Factor Promotes Tumor Invasion and Metastasis via the Rho-Dependent Pathway

Departments of ¹ Surgery and ² Molecular Biochemistry, Hokkaido University Graduate School of Medicine and ³ GeneticLab Co., Ltd., Sapporo, Japan

Requests for reprints: Jun Nishihira, Department of Molecular Biochemistry, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan. Phone: 81-11-611-3967; E-mail: j_nisihi{at}med.hokudai.ac.jp.

Purpose: Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system but also in tumorigenesis. In this study, we investigated the potential role of MIF in association with tumor invasion and metastasis.

Methods: To assess the function of MIF, we knocked down the MIF mRNA using small interfering RNA (siRNA). Twenty-one base siRNA specific for the mRNA sequence of mouse MIF was introduced to a murine colon cancer cell line, colon 26. Tumor cell invasion was evaluated using a transwell method (8-µm pores) coated with Matrigel on the upperside membrane and with fibronectin on the underside membrane. Moreover, we investigated the signal transduction of lysophosphatidic acid (LPA) relevant to the Rho-dependent pathway and further examined the effect of MIF siRNA on this signal transduction system. In vivo, the tumor cells were pretreated with MIF siRNA and injected into the portal vein, and the effects on metastasis to the liver were evaluated.

Results: We found that MIF siRNA markedly reduced the invasion of the cells from the upperside to lowerside membranes. We revealed that the Rho-dependent pathway activated by LPA was suppressed by MIF siRNA. Next, we found that the tyrosine-phosphorylation of focal adhesion kinase and LPA-induced expressions of integrin ß1 were significantly suppressed by MIF siRNA. In vivo, metastasis to the liver was significantly inhibited by pretreatment of the cells with MIF siRNA.

Conclusion: Taken together, these results suggest that MIF promotes tumor invasion and metastasis via the Rho-dependent pathway.

Key Words: lysophosphatidic acid • macrophage migration inhibitory factor • RNA interference

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