Stromal cell‐derived factor‐1/CXC receptor 4 and β1 integrin interaction regulates urokinase‐type plasminogen activator expression in human colorectal cancer cells

AbstractThe stromal cell‐derived factor‐1 (SDF‐1)/CXC receptor 4 (CXCR4) axis has been shown to play a role in colorectal cancer progression. In addition, the protease urokinase‐type plasminogen activator (uPA) is an important factor in tumor cell invasion and metastasis. However, the mechanism by which SDF‐1 mediates uPA expression in human colorectal cancer cells remains unknown. We investigated the molecular mechanism governing the interaction between SDF‐1 stimulation and uPA expression in three human colon cancer cell lines (DLD‐1, SW48, and COLO 205). We found that SDF‐1 stimulation led to an increase in the expression and secretion of uPA in these cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of p38 mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/Akt pathways are critical for SDF‐1‐induced uPA expression. Analysis of transcription factor binding using ELISA and chromatin immunoprecipitation assays revealed that SDF‐1 increased Sp1‐ and AP‐1‐DNA‐binding activities in DLD‐1 cells. Inhibition of Sp1 and AP‐1 activation blocked the SDF‐1‐induced expression and activity of the uPA promoter. The effect of SDF‐1 on DLD‐1 signaling and uPA expression was mediated by the CXCR4/β1 integrin axis. In summary, our findings elucidate the mechanisms of SDF‐1/CXCR4 downstream signaling and provide insights into the function of SDF‐1 in colon cancer cells. J. Cell. Physiol. 227: 1114–1122, 2012. © 2011 Wiley Periodicals, Inc.