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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Acknowledgements
This work was supported by the Korea Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center (TIMRC) at Seoul National University College of Medicine and through the Research Center for Women's Disease (RCWD; SRC program (R11-2005-017-02003-0)) at Sookmyung Women's University.
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Kim, KE., Song, H., Kim, T. et al. Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines. Oncogene 26, 1468–1476 (2007). https://doi.org/10.1038/sj.onc.1209926
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DOI: https://doi.org/10.1038/sj.onc.1209926
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