Urinary-Type Plasminogen Activator Receptor (uPA/R)/α3β1 Integrin Signaling and Oral Tumor Progression.

Oral squamous cell carcinoma (OSCC) has 50% 5-year survival rate,highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions both as a proteinase receptor and an integrin ligand,modifying proteolysis,migration,integrin signaling and cellular transcription. In the current study,uPAR expression levels were modified in OSCC cells,followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors,with ill-defined borders,cytologic atypia,and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC demonstrated a statistically significant association between uPAR and α3 integrin co-localization in areas exhibiting ERK phosphorylation,suggesting that uPAR/α3 integrin interaction potentiates ERK signaling in vivo. This is supported by cDNA microarray analysis which showed differential expression of 148 genes (113 up,35 down). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors,proteinases/inhibitor and matrix components in uPAR-overexpressing tumors. Together these results support a model wherein increased uPAR expression promotes α3β1 integrin association,resulting in increased MAPK signaling and transcriptional activation,leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC.