S100A8 and S100A9 Promotes Invasion and Migration through p38 Mitogen-Activated Protein Kinase-Dependent NF-κB Activation in Gastric Cancer Cells

Abstract

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.

Effects of silencing S100A8 and S100A9 with small interfering RNA on the migration of CNE1 nasopharyngeal carcinoma cells

“…In addition, MMP7 expression was somewhat reduced, indicating that endogenous S100A8 and S100A9 promoted the migration of CNE1 NPC cells; this is consistent with the conclusion that S100A8/A9 promotes colon tumor cell metastasis, as reported by Ichikawa et al (25). S100A8 and S100A9 may promote cell migration and invasion through p38 MAPK-dependent nuclear factor-κB activation (21). Further investigation is required to determine the molecular mechanisms underlying the promotion of CNE1 NPC cell migration by endogenous S100A8 and S100A9.…”

“…Further investigation is required to clarify the differential roles of S100A8 and S100A9 on MMP7 expression in CNE1 cells. Yong and Moon (17) demonstrated that expression level of MMP2 was decreased by 83% with S100A9 siRNA and by 52% with S100A8 siRNA, indicating that S100A8/A9 may increase MMP2 and MMP7, although this is inconsistent with the results reported by Kwon et al (21).…”

“…Mounting evidence indicates that MMP family members are involved in tumor invasion and metastasis (17). MMPs are proteolytic enzymes capable of degrading extracellular matrix proteins (21), whose activity is implicated in a number of key normal and pathological processes, including tumor growth, progression, and metastasis and dysregulated angiogenesis (22). Enzymatic degradation of the extracellular matrix is a crucial step in cancer invasion and metastasis.…”

Protein S100-A8: A potential metastasis-associated protein for breast cancer determined via iTRAQ quantitative proteomic and clinicopathological analysis

“…The present study implemented the Cox proportional hazards model, which demonstrated that protein S100-A8 is not an independent risk factor for prognosis in breast cancer. S100-A8 also assembles heterodimers with S100-A9, which increases matrix metalloproteinase (MMP)-2 or MMP-12 expression and activity to promote tumor cell migration and invasion (36,37). This suggests that the interaction of S100-A8 within heterodimers is able to affect its activity during the process of breast cancer progression.…”

RAGE and Its Ligands in Melanoma

“…Recent studies have also shown that they play significant roles in cancer where they promote tumor growth and metastasis in a large number of cancers such as in breast, prostate and pancreatic cancer [232][233][234][235][236][237][238]. In tumors, recent studies have shown that S100A8/A9 regulates the accumulation of myeloid-derived suppres-sor cells (MDSC), and also promote the expansion of these cells, resulting in increased tumor growth [239][240][241][242][243].…”