There have been reports of strong correlations between poor prognosis in various cancers and concomitant expression of urokinase-type plasminogen activator (uPA) and its surface receptor (uPAR). In a previous study, we found that cells overexpressing both uPAR and uPA mRNA were more invasive and aggressive in an in vivo experimental metastasis model. In immunohistochemical studies, the uPA system has been found to be significantly associated with mode of invasion and secondary regional lymph node metastasis of squamous cell carcinoma (SCC) in the oral cavity. The majority of studies of the uPA system in oral SCC have shown that patterns of expression of the uPA system correlate with metastatic ability of cancer cells or clinicopathological observations. In the present study, we examined overexpression of uPAR mRNA in OSC-19 cells derived from human oral SCC, and examined the function of uPAR using antisense oligodeoxynucleotides (AS-ODNs) and small interfering RNA (siRNA). We found that uPAR is required for invasion and metastasis of OSC-19 cells in the present in vivo models. Treating OSC-19 cells with AS-ODNs targeting uPAR resulted in a dramatic decrease of uPAR mRNA expression. Furthermore, pretreatment with AS-ODNs inhibited progression of OSC-19 cells in experimental models. Additionally, transfection of cells with uPAR siRNA inhibited degradation of fibronectin. We observed an especially strong relationship between the uPA system and initial invasion of oral cancer cells. These results suggest that overexpression of uPAR increases the invasiveness and metastasis of OSC-19 cells, and that uPAR is a promising therapeutic target for regulation of progression of oral cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]