Gastric cancer is one of the most common malignancies and is a frequent cause of cancer-related death in Korea. Cure rate of gastric cancer is quite low because of local invasion and metastasis. S100 proteins are calcium-binding proteins which exert various calcium-mediated cellular functions including cell growth, differentiation, migration and signal transduction. S100A8 and S100A9 are overexpressed in many human tumors and have been shown to be implicated in tumor development or progression. In the present study, we investigated the role of S100A8 and S100A9 in invasive phenotype of a human gastric cancer cell line, SNU484. Expression of S100A8 and S100A9 were detected in SNU484 cells. When the expression of these proteins was suppressed by small-interfering RNA (siRNA) targeting S100A8 or S100A9, the invasive and migratory phenotypes of SNU484 cells were significantly inhibited. The siRNAs for S100A8 and S100A9 inhibited matrix metalloproteinase (MMP)-2 expression in SNU484 cells as evidenced by gelatin zymogram assay, immunoblot analysis and reverse transcription (RT)-PCR. These results demonstrate that S100A8 and S100A9 are required for transcriptional activation of MMP-2 gene in SNU484 cells. Taken together, this study revealed a functional contribution of S100A8 and S100A9 proteins to processes required for malignant progression including invasion, migration and proteinase expression in SNU484 human gastric cancer cells.