The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis

This article reviews the role of urokinase-type plasminogen activator recep tor (uPAR) and its protein, mRNA, cDNA, genomic organization, promoter. tra nscription activation factors and signal transduction, The uPAR has been im plicated in several biological processes including angiogenesis. monocyte m igration, cancer metastasis, trophoblast implantation and wound healing. It is a specific cell surface receptor for its ligand uPA which catalyzes the formation of plasmin from plasminogen to generate the proteolytic cascade that contributes to the breakdown of extracellular matrix, a key step in ca ncer metastasis. The uPAR is a 55-60 kDa glycoprotein organized as three ho mologous cysteine-rich domains. It attaches to the plasma membrane via a co valent linkage to a glycosyl-phosphatidylinositol (GPI) moiety and appears to play an important role in transmembrane signalling, The 1.4-kb human uPA R cDNA and 21.23-kb genomic DNA have been cloned and the gene contains seve n exons, The uPAR promoter region was defined in a 188 bp fragment between bases -141 and +47 relative to the transcription start site, Binding of tra nscription factors (Sp1, AP-2, NF kappaB and two AP-I) to the uPAR promoter region activates the basal transcription of the gene, There is a strong co rrelation between uPAR expression and the invasive cancer cell phenotype. u PAR may play a critical role in the process of cancer invasion and metastas is, as antisense uPAR mRNA can inhibit cancer spread in vitro and in vivo. These studies may provide a novel therapeutic target for blocking cancer in vasion and metastasis. (C) 2001 John Wiley & Sons. Inc.