Inhibition of endothelial cell migration through the down‑regulation of MMP-9 by A-kinase anchoring protein 12

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix (ECM) molecules. ECM degradation is associated with tumor metastasis and angiogenesis. Therefore, the regulation of MMPs is of potential benefit in the treatment of various diseases, including cancer. A-kinase anchoring protein 12 (AKAP12) has been identified as a potential tumor suppressor. However, the function of AKAP12 as a tumor suppressor is not well understood. Herein, to determine the relationship between AKAP12 and MMP-9 in cancer, we first investigated the expression of MMP-9 under normoxic and hypoxic conditions in human fibrosarcoma cells. The expression of MMP-9 was not detected under normoxic conditions.; however, it was markedly increased under hypoxia in HT1080 cells. The effect of AKAP12 on the expression of MMP-9 was subsequently investigated. Hypoxia-induced MMP-9 mRNA expression was significantly reduced by overexpression of AKAP12, as was MMP-9 protein expression. In addition, when the AKAP12 transfectant-conditioned media (CM) were transferred into human endothelial cells, cell migration was significantly inhibited compared to the control group. Notably, the inhibition of AKAP12 expression by siRNA targeting AKAP12 resulted in an increase in the expression of active MMP-2 under normoxia, as well as of MMP-9. Endothelial cell migration was also strongly increased by treatment with CM of siRNA against AKAP12, as compared to the control group. Taken together, the results indicate that AKAP12 is involved in the regulation of endothelial cell migration through the inhibitory regulation of MMP-9 expression in tumor cells.