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Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines

Department of Life Science, Sookmyung Women's University, Yongsan-ku, Seoul, Korea.
Oncogene (Impact Factor: 8.56). 04/2007; 26(10):1468-76. DOI: 10.1038/sj.onc.1209926
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ABSTRACT Cell migration and angiogenesis are key steps in tumor metastasis. However, the mechanism of migration regulated by vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is not completely understood. This study examined the relationship between VEGF and migration, along with the mechanism involved in the VEGF-regulated migration of human gastric cancer cells. The level of cell migration was increased by recombinant human (rh)VEGF-165 in the VEGF receptor-2-expressing SNU-601 cells. Interleukin (IL)-18 is associated with the malignant progression of tumors. Accordingly, this study examined the effect of IL-18 on the migration of cancer cells in order to identify the factors involved in VEGF-enhanced migration. Inhibiting IL-18 markedly reduced the level of VEGF-enhanced migration, and IL-18 increased cell migration directly through filamentous-actin polymerization and tensin downregulation. It was confirmed that rhVEGF-165 increased IL-18 production significantly. An antioxidant and an extracellular signal-regulated kinase (ERK)1/2-specific inhibitor blocked rhVEGF-165-enhanced IL-18 production. Accordingly, rhVEGF-165 increased the generation of region of interest (ROI) and activated the ERK1/2 pathway. These results suggest that rhVEGF-165 enhances IL-18 production via the generation of ROI and ERK1/2 phosphorylation, which results in the increased migration of gastric cancer cells.

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    • "Higher expression levels of IL-18 have been detected in various cancer cells, such as those in gastric cancer (Ye et al., 2007) and breast cancer (Eissa et al., 2005). Further analysis has shown that IL-18 promotes the expression of vascular endothelial growth factor and degradation of the extracellular matrix to accelerate the process of cancer angiogenesis and migration (Alexandrakis et al., 2004; Jung et al., 2006; Cho et al., 2006; Kim et al., 2007). The data obtained recently also indicated that IL-18 interacts with phosphorylation ERK1/2 (Amin et al., 2007), p38 MAPK, and endogenous oxygen species (reactive oxygen intermediate)signaling pathways (Jung et al., 2006) to induce the apoptosis of immune cells in the tumor immune escape (Yoon et al., 2004). "
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    • "Similarly, the dual eVect of IL-18 in tumor progression is illustrated by its ability to stimulate natural killer and T cells which eliminate nascent tumor cells on the one hand, yet to display pro-carcinogenic functions on the other, that include promotion of VEGF production , which itself stimulates IL-18 mRNA synthesis in a dose-dependent manner. (Kim et al. 2007). IL-18 also induces MMP-9 expression, and may thereby be a signiWcant player in tumor cell migration, invasion and metastasis (Park et al. 2007). "
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