Archives of Pharmacal Research

, Volume 30, Issue 1, pp 75–81 | Cite as

Roles of calcium-binding proteins, S100A8 and S100A9, in invasive phenotype of human gastric cancer cells

  • Hae-Young Yong
  • Aree Moon
Articles Drug Development


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.

Key words

S100A8 S100A9 Invasion MMP-2 Gastric cancer 


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  1. Arai, K., Teratani, T., Kuruto-Niwa, R., Yamada, T, and Nozawa, R., S100A9 expression in invasive ductal carcinoma of the breast: S100A9 expression in adenocarcinoma is closely associated with poor tumor differentiation.Eur. J. Cancer, 40, 1179–1187 (2004).PubMedCrossRefGoogle Scholar
  2. Arai, K., Teratani, T., Nozawa, R., and Yamada, T., Immunohis-tochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation.Oncol. Rep., 8, 591–596 (2001).PubMedGoogle Scholar
  3. Arai, K., Yamada, T., and Nozawa, R., Immunohistochemical investigation of migration inhibitory factor-related protein (MRP)-14 expression in hepatocellular carcinoma.Med. Oncol., 17, 183–188 (2000).PubMedCrossRefGoogle Scholar
  4. Bernhard, E. J., Gruber, S. B., and Muschel, R. J., Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells.Proc. Natl. Acad. Sci., 91, 4293–4297 (1994).PubMedCrossRefGoogle Scholar
  5. Cross, S. S., Hamdy, F. C., Deloulme, J. C., and Rechman, I., Expression of S100 proteins in normal human tissues and common cancers using tissue microarrays: S100A6, S100A8, S100A9 and S100A11 are all overexpressed in common cancers.Histopathology, 46, 259–269 (2005).CrossRefGoogle Scholar
  6. Davey, G. E., Murmann, P., Hoechli, M., Tanaka, T., and Heizmann, C. W., Calcuim-dependent translocation of S100A11 requires tubulin filaments.Biochim. Biophys. Acta., 1498, 220–232 (2000).PubMedCrossRefGoogle Scholar
  7. Donato, R., S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.Int. J. Biochem. Cell Biol., 33, 637–668 (2001).PubMedCrossRefGoogle Scholar
  8. El-Rifai, W., Moskaluk, C. A, Abdrabbo, M. K., Harper, J., Yoshida, C., Riggins, G. J., Frierson Jr, H. F., and Powell., S. M., Gastric Cancers Overexpress S100A Calcium-binding Proteins.Cancer Res., 62, 6823–6826 (2002).PubMedGoogle Scholar
  9. Fidler, I. J., Critical factors in the biology of human cancer metastasis.Cancer Res., 50, 6130–6138, 1990.PubMedGoogle Scholar
  10. Gebhardt, C., Breitenbach, U., Tuckermann, J. P., Dittrich, B. T., Richter, K. H., and Angel, P., Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis.Oncogene, 21, 4266–4276 (2002).PubMedCrossRefGoogle Scholar
  11. Hermani, A., De Servi, B., Medunjanin, S., Tessier, P. A., and Mayer, D., S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells.Exp. Cell Res., 312, 184–97 (2006).PubMedCrossRefGoogle Scholar
  12. Hermani, A., Hess, J., De servi, B., Medunjanin, S., Grobholz, R., Trojan, L., Angel, P., and Mayer, D., The calcium-binding proteins S100A8 and S100A9 are novel diagnostic markers that are co-expressed with the receptor for advanced glycation end products (RAGE) in human prostate cancer.Clin. Cancer Res., 11, 5146–5152 (2005).PubMedCrossRefGoogle Scholar
  13. Hofmann, M. A., Drury, S., Fu, C., Qu, W., Toguchi, A., Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P., Neurath, M. F., Slattery., T, Beach, D., McClary, J., Nagashima, M., Morser, J., Stern, D., and Schmidt, A. M., RAGE mediates a novel proinflammatory axis: a central cell surface receptor forSIOO/calgranulin polypeptides.Cell, 97, 889–901 (1999).PubMedCrossRefGoogle Scholar
  14. Ji, F., Chen, Y. L., Jin, E. Y., Wang, W. L., Yang, Z. L., and Li, Y. M., Relationship between matrix metalloproteinase-2 mRNA expression and clinicopathological and urokinase-type plasminogen activator system parameters and prognosis in human gastric cancer.Gastric cancer, 11, 3222–3226 (2005).Google Scholar
  15. Kerkhoff, C., Klempt, M., Kaever, V., and Sorg, C., The two calcium-binding proteins, S100A8 and S100A9 are involved in the metabolism of arachidonic acid in human neutrophils.J. Biol. Chem., 274, 32672–32679 (1999).PubMedCrossRefGoogle Scholar
  16. Kim, M. S., Lee E. J., Choi Kim, H. R., and Moon, A., p38 kinase is a key signaling molecule for H-ras-induced cell motility and invasive phenotype in human breast epithelial cell.Cancer Res., 63, 5454–5461 (2003).PubMedGoogle Scholar
  17. Li, C., Zhang, F., Lin, M., and Liu, J., Induction of S100A9 gene expression by cytokine oncostatin M in breast cancer cells through the STAT3 signaling cascade.Breast Cancer Res. Treat, 87, 123–134 (2004).PubMedCrossRefGoogle Scholar
  18. Li, Z. H. and Bresnick, A. R., The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA.Cancer Res., 66, 5173–5180 (2006).PubMedCrossRefGoogle Scholar
  19. Liotta, L. A., Steeg, P. S., and Stetler-Stevenson, W. G., Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation.Cell, 64, 327–336 (1991).PubMedCrossRefGoogle Scholar
  20. Mandinova, A., Atar, D., Schfer, B. W., Spiess, M., Aebi, U., and Heizmann, C. W., Distinct subcellular localization of calcium binding S100 proteins in human smooth muscle cells and their relocation in response to rise in intracellular calcium.J. Cell Sci., 111, 2043–2054 (1998).PubMedGoogle Scholar
  21. Monig, S. P., Baldaus, S. E., Hennecken, J. K., Spiecker, D. B., Grass, G., Schneider, P. M., Thiele, J., Dienes, H. P., and Holschr, A. H., Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma.Histopathlogy, 39, 597–602 (2001).CrossRefGoogle Scholar
  22. Moon, A., Kim, M. S., Kim, T. G, Kim, S. H., Kim, H. E., Chen, Y. Q., and Choi Kim, H. R., H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: a role for MMP-2 in the H-ras-induced invasive phenotype.Int. J. Cancer, 85, 176–181 (2000).PubMedGoogle Scholar
  23. Mueller, A., Bachi, T., Hochli, M., Schfer, B. W., and Heizmann, C. W., Subcellular distribution of S100 proteins in tumor cells and their relocation in response to calcium activation.Histochem. Cell Biol., 111, 453–459 (1999).PubMedCrossRefGoogle Scholar
  24. Nomura, H., Fujimoto, N., Seiki, M., Mai, M., and Okada, Y., Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas.Int. J. Cancer, 69, 9–16 (1996).PubMedCrossRefGoogle Scholar
  25. Ott, H. W., Lindner, H., Sarg, B., Mueller-Holzner, E., Abendstein, B., Bergant, A., Fessler, S., Schwaerzler, P., Zeimet, A., Marth, C., and Illmensee, K., Calgranulins in cystic fluid and serum from patients with ovarian carcinomas.Cancer Res., 63, 7507–7514 (2003).PubMedGoogle Scholar
  26. Roth, J., Burwinkel, F., van den Bos, C., Goebeler, M., Vollmer, E., and Sorg, C., MRP8 and MRP14, S100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner.Blood, 82, 1875–1883 (1993).PubMedGoogle Scholar
  27. Shin, I., Kim, S., Song, H., Kim, H. R., and Moon, A., H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells.J. Biol. Chem., 280, 14675–14683 (2005).PubMedCrossRefGoogle Scholar
  28. Song, H., Ki, S. H., Kim, S. G., and Moon, A., Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells.Cancer Res., 66, 10487–10496 (2006).PubMedCrossRefGoogle Scholar
  29. Steller-Stevenson, W. G., Type-IV collagenases in tumor invasion and metastasis.Cancer Metast Rev., 9, 289–303 (1990).CrossRefGoogle Scholar
  30. Sundblad, A. and Ricci, L., MMP-2 expression (type IV collagenase) in gastric cancer.Acta. Gastroeuterol Latinoam., 28, 287–290 (1998).Google Scholar
  31. Taguchi, A., Blood, D. C., Toro, G., Canet, A., Lee, D. C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M. A., Kislinger, T., Ingram, M., Lu, A., Ranaka, H., Hori, O., Ogawa, S., Stem, D. M., and Schmidt, A. M., Blockade of RAGE- amphoterin signaling suppresses tumor growth and metastases.Nature, 405, 354–360 (2000).PubMedCrossRefGoogle Scholar
  32. Takahashi, Y., Kitadai, Y., Ellis, L. M., Bucana, C. D., Fidler, I. J., and Mai, M., Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma.Jpn. J. Cancer Res., 93, 1258–1265 (2002).PubMedGoogle Scholar
  33. Tryggvason, K., Type-IV collagenase in invasive tumors.Breast CancerRes. Treat, 24, 209–218 (1993).CrossRefGoogle Scholar
  34. Tsuchiya, A., Kikuchi, Y., Ando, Y., Yoshida, T., and Abe, R., Lymph node metastases in gastric cancer invading the submucosal layer.Eur. J. Surg. Oncol., 21, 248–250 (1995).PubMedCrossRefGoogle Scholar
  35. Ura, H., Bonfil, R. D., Reich, R., Reddel, R., Pfeifer, A., Harris, C. C., and Klein-Szanto, A. J. P., Expression of type IV collagenases and procollagen genes and its correlation with the tumorigenic, invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells.Cancer Res., 49, 4615–4621 (1989).PubMedGoogle Scholar
  36. Vogl, T., Ludwing, S., Geobeler, M., Strey, A., Thorey I. S., Reichelt, R., Foell, D., Gerke, V., Manitz, M. P., Nacken, W., Werner, S., Sorg, C., and Roth, J., MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes.Blood, 104, 4260–4268 (2004).PubMedCrossRefGoogle Scholar
  37. Yasuda, K., Shiraishi, N., Suematsu, T, Yamaguchi, K., Adachi, Y., and Kitano, S., Rate of detection of lymph node metastasis is correlated with the depth of submucosal invasion in early stage gastric carcinoma.Cancer, 85, 2119–2123 (1999).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  1. 1.College of PharmacyDuksung Women’s UniversitySeoulKorea

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