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Macrophage Inhibitory Cytokine-1 Induces the Invasiveness of Gastric Cancer Cells by Up-Regulating the Urokinase-type Plasminogen Activator System¹

Laboratories of Anticancer Research [D. H. L., T. H. K., J. J. L., J-H. L.], and Immunology [Y. Y., K-Y. K., S. M. S., I. C.], Korea Research Institute of Bioscience and Biotechnology, Yusung, Daejon 305-333; Departments of Anatomy [S. J. L., Y. H. L.] and Pathology [K. S. S.], College of Medicine, Chungnam National University, Daejon 301-131; and Department of Molecular Biology, Pusan National University, Pusan 609-735, [Y-J. K.] Republic of Korea

In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor ß superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.

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