Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system

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Title
Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system
Author(s)
Dong Hoon Lee; Young Yang; S J Lee; Kun Yong Kim; Tae Hyeon Kim; Sun Mi Shin; K S Song; Y H Lee; Y J Kim; Jung Joon Lee; In Pyo Choi; Jeong-Hyung Lee
Bibliographic Citation
Cancer Research, vol. 63, no. 15, pp. 4648-4655
Publication Year
2003
Abstract
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 β 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.
ISSN
0008-5472
Publisher
Amer Assoc Cancer Research
Type
Article
Appears in Collections:
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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