S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-κB activation in gastric cancer cells
- 512 Downloads
S100A8 and S100A9 (S100A8/A9) are low-molecular weight members of the S100 family of calcium-binding proteins. Recent studies have reported S100A8/A9 promote tumorigenesis. We have previously reported that S100A8/A9 is mostly expressed in stromal cells and inflammatory cells between gastric tumor cells. However, the role of environmental S100A8/A9 in gastric cancer has not been defined. We observed in the present study the effect of S100A8/A9 on migration and invasion of gastric cancer cells. S100A8/ A9 treatment increased migration and invasionat lower concentrations that did not affect cell proliferation and cell viability. S100A8/A9 caused activation of p38 mitogenactivated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The phosphorylation of p38 MAPK was not affected by the NF-κB inhibitor Bay whereas activation of NF-κB was blocked by p38 MAPK inhibitor SB203580, indicating that S100A8/A9-induced NF-κB activation is mediated by phosphorylation of p38 MAPK. S100A8/A9-induced cell migration and invasion was inhibited by SB203580 and Bay, suggesting that activation of p38 MAPK and NF-κB is involved in the S100A8/A9 induced cell migration and invasion. S100A8/A9 caused an increase in matrix metalloproteinase 2 (MMP2) and MMP12 expression, which were inhibited by SB203580 and Bay. S100A8/A9-induced cell migration and invasion was inhibited by MMP2 siRNA and MMP12 siRNA, indicating that MMP2 and MMP12 is related to the S100A8/A9 induced cell migration and invasion. Taken together, these results suggest that S100A8/A9 promotes cell migration and invasion through p38 MAPKdependent NF-κB activation leading to an increase of MMP2 and MMP12 in gastric cancer.
Keywordsgastric cancer cells MMP NF-κB p38MAPK S100A8/A9
Unable to display preview. Download preview PDF.
- Ang, C.W., Nedijadi, T.A., Sheikh, A.M., Tweedle, E., Tonack, S., Honap, S.E., Jenkins, R., Park, B.K., Schwarte-Waldhoff, I., Khattak, I., et al. (2010). Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells. Carcinogenesis 31, 1541–1551.PubMedCrossRefGoogle Scholar
- Ghavami, S., Kerkhoff, C., Chazin, W.J., Kadkhoda, K., Xiao, W., Zuse, A., Hashemi, M., Eshraghi, M., Schulze-Osthoff, K., Klonisch, T., et al. (2008a). S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2. Biochim. Biophys. Acta. 1783, 297–311.PubMedCrossRefGoogle Scholar
- Ghavami, S., Rashedi, I., Dattilo, B.M., Eshraghi, M., Chazin, W.J., Hashemi, M., Wesselborg, S., Kerkhoff, C., and Los, M. (2008b). S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J. Leukocyte Biol. 83, 1484–1492.PubMedCrossRefGoogle Scholar
- Kerkela, E., Ala-aho, R., Klemi, P., Grenman, S., Shapiro, S.D., Kahari, V.M., and Saarialho-Kere, U. (2002). Metalloelastease (MMP-12) expression by tumour squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome. J. Pathol. 198, 258–269.PubMedCrossRefGoogle Scholar
- Moon, A., Yong, H.Y., Song, J.I., Cukovic, D., Salagrama, S., Kaplan, D., Putt, D., Kim, H., Dombkowski, A., and Kim, H.R. (2008). Global gene expression profiling unveils S100A8/A9 as candidate markers in H-ras-mediated human breast epithelial cell invasion. Mol. Cancer Res. 6, 1544–1553.PubMedCrossRefGoogle Scholar
- Rychman, C., Vandal, K., Rouleau, P., Talbot, M., and Tessier, P.A. (2003). Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutophilchemotaxis and adhesion. J. Immunol. 170, 3233–3242.Google Scholar
- Sheikh, A.A., Vimalachandran, D., Thompson, C.C., Jenkins, R.E., Nedjadi, T., Shekouh, A., Campbell, F., Dodson, A., Prime, W., Crnogorac-Jurcevic, T., et al. (2007). The expression of S100A8 in pancreatic cancer-associated monocyte is associated with the Smad4 status of pancreatic cancer cells. Proteomics 7, 1929–1940.PubMedCrossRefGoogle Scholar
- Takada, Y., Singh, S., and Aggarwal, B.B. (2004). Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in downregulation of NF-kappaB-mediated gene expression and upregulation of apoptosis. J. Biol. Chem. 279, 15096–15104.PubMedCrossRefGoogle Scholar