These in vivo observations are consistent with the findings in cl

These in vivo observations are consistent with the findings in clinical specimens and further support the hypothesis that AEG 1 sellectchem is in volved in the metastatic cascade of HNSCC. AEG 1 suppression downregulates MMP1 production To determine the downstream targets of AEG 1 that contribute to invasion and metastasis pathways in HNSCC cells, we performed a microarray comparison. RT QPCR analysis also revealed a reduction in MMP1 mRNA in SB cells and FB cells. In addition, AEG between the gene expression profiles of SB cells and SCt cells. The expression level of MMP1 in SB cells was downregulated Inhibitors,Modulators,Libraries by approximately 3. 3 fold, as compared to that in SCt cells 1 knockdown caused a remarkable reduction of secreted MMP1 protein in the cell conditioned culture media for both SAS and FaDu cells.

Immunohisto chemical staining of MMP1 revealed a reduced positive signal in tumor xenografts and pulmonary metastatic lesions generated from AEG 1 knockdown HNSCC cells, as compared to the cytosolic and juxtacellular staining of MMP1 observed in lesions arising from con trol cells. Also, incorporation of MMP in hibitor I hampered the Inhibitors,Modulators,Libraries invasion abilities of SAS and FaDu cells in transwell assays. As MMPs are considered to be involved in both invasion and metastasis, MMP1 may be a down stream effector of AEG 1 in determining the aggressive phenotype of HNSCC. AEG 1 expression increases phosphorylation of the p65 subunit of NF B and enhances p65 binding to the MMP1 promoter We hypothesized Inhibitors,Modulators,Libraries that AEG 1 may affect MMP1 expres sion through NF B and AP1, since the promoter of MMP1 Inhibitors,Modulators,Libraries harbors regulation sites for these two transcrip tion factors.

Western blotting revealed that the levels of the phosphorylated p65 subunit Inhibitors,Modulators,Libraries of NF B in SB cells and FB cells were 68. 84% and 45. 64% that of the control counterparts, re spectively. However, phosphorylation status of c jun, Akt and GSK3B were unaffected by AEG 1 knockdown. Also, the phosphorylation status of p65 at serine 468 and the level of phosphorylated IB are unchanged free copy after AEG 1 knockdown in HNSCC cell lines. These observations prompted us to exam ine the relationship between AEG 1 expression and the phosphorylation status of p65 at serine 536 in clinical specimens of HNSCC. A spatial correlation between AEG 1 and phosphorylated p65 was evident in the high AEG 1 expressing group, while the phosphorylated p65 signals in the low and nil AEG 1 expressing cases were primarily observed at the peripheral basal cells of the neoplastic nests. AEG 1, phosphorylated p65 and MMP1 were co localized in the enrolled cohort of OSCC, and these associations were statistically significant.

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