HIF-1α Acts Downstream of TNF-α to Inhibit Vasodilator-Stimulated Phosphoprotein Expression and Modulates the Adhesion and Proliferation of Breast Cancer Cells

Metastasis is the leading cause of death in breast cancer patients. Recent evidence suggests that inflammation-related cytokine tumor necrosis factor-alpha (TNF-alpha) is implicated in tumor invasion and metastasis, but the mechanism of its involvement remains elusive. In this study, we employed MCF-7 breast cancer cells as an experimental model to demonstrate that TNF-alpha inhibits breast cancer cell adhesion and cell proliferation through hypoxia inducible factor-1alpha (HIF-1 alpha) mediated suppression of vasodilator-stimulated phosphoprotein (VASP). We observed that TNF-alpha treatment attenuated the adhesion and proliferation of MCF-7 cells it also dramatically increased HIF-1 alpha, expression and decreased VASP expression. Through a variety of approaches, including promoter assay, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP), we identified VASP as a direct target gene of HIF-1 alpha. In addition, we confirmed that HIF-1 alpha mediated the repression of VASP expression by TNF-alpha in MCF-7 cells. We also demonstrated that exogenous VASP expression or knockdown of HIF-1 alpha relieved TNF-alpha induced inhibition of cell adhesion and proliferation. We identified a novel TNF-alpha/HIF-1 alpha/VASP axis in which HIF-1 alpha acts downstream of TNF-alpha to inhibit VASP expression and modulate the adhesion and proliferation of breast cancer cells. These data provide new insight into the potential anti-tumor effects of TNF-alpha.