Global Gene Expression Profiling Unveils S100A8/A9 as Candidate Markers in H-Ras-Mediated Human Breast Epithelial Cell Invasion

Abstract

The goal of the present study is to unveil the gene expression profile specific to the biological processes of human breast epithelial cell invasion and migration using an MCF10A model genetically engineered to constitutively activate the H-ras or N-ras signaling pathway. We previously showed that H-Ras, but not N-Ras, induces MCF10A cell invasion/migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. Thus, these cell lines provide an experimental system to separate the gene expression profile associated with cell invasion apart from cell proliferation/transformation. Analysis of whole human genome microarray revealed that 412 genes were differentially expressed among MCF10A, N-Ras MCF10A, and H-Ras MCF10A cells and hierarchical clustering separated 412 genes into four clusters. We then tested whether S100A8 and S100A9, two of the genes which are most highly up-regulated in an H-Ras -specific manner, play a causative role for H-Ras -mediated MCF10A cell invasion and migration. Importantly, small interfering RNA -mediated knockdown of S100A8/A9 expression significantly reduced H-Ras -induced invasion/ migration. Conversely, the induction of S100A8/A9 expression conferred the invasive/migratory phenotype to parental MCF10A cells. Furthermore, we provided evidence of signaling cross-talk between S100A8/A9 and the mitogen-activated protein kinase signaling pathways essential for H-Ras -mediated cell invasion and migration. Taken together, this study revealed S100A8/A9 genes as candidate markers for metastatic potential of breast epithelial cells. Our gene profile data provide useful information which may lead to the identification of additional potential targets for the prognosis and/or therapy of metastatic breast cancer. (Mol Cancer Res 2008;6(10):1544 -53)

Denbinobin, a phenanthrene from dendrobium nobile, inhibits invasion and induces apoptosis in SNU-484 human gastric cancer cells

“…Our previous studies identified S100A8 and S100A9 as candidate markers for cell invasion in breast epithelial cells (33) and showed that these proteins up-regulated MMP-2, causing invasive phenotype in SNU-484 cells (25). The results obtained from this study demonstrated a dose-dependent down-regulation of S100A8 by denbinobin in SNU-484 cells, suggesting the involvement of S100A8 in the denbinobininduced invasive phenotype.…”

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

“…Enzymatic degradation of the extracellular matrix is a crucial step in cancer invasion and metastasis. Another previous study supports the hypothesis that S100A8 is more closely associated with MMP9 expression mediated by the extracellular-signal-regulated kinase pathway, whilst S100A9 has a major role in MMP2 upregulation that is dependent on p38 mitogen-activated protein kinase (MAPK) signaling (23). A further study reported that S100A8 and S100A9 contribute to colorectal carcinoma cell survival and migration via the Wnt/β-catenin pathway.…”

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

“…Although S100A8/A9 protein has been shown to exert apoptotic effect against various tumor cells including colon carcinoma cells (Ghavami et al, 2004) and breast cancer cells and neuroblastoma cells (Ghavami et al, 2008a), the effect of S100A8/ A9 on cell viability has been reported to be dependent on concentration exposed. S100A8/A9 resulted in significantly reduced cell viability at concentration above 50 μg/ml, while it at concentration lower than 25 μg/ml promotes proliferation and migration of various cancer cells (Ghavami et al, 2008b;Hermani et al, 2006;Moon et al, 2008). We observed that S100A8/ A9 at high concentration (30 μg/ml) exerts apoptotic effects in gastric cancer cells (Fig.…”