title: Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas.
abstract: Oral cavity cancer is among the most frequently diagnosed cancers worldwide and urinary-type plasminogen activator receptor (uPAR) is clinically associated with more invasive tumors and enhanced lymph node metastasis. We seek to further elucidate the mechanism of by which uPAR promotes cell aggressiveness in the unique context of oral squamous cell carcinoma (OSCC). The contribution of uPAR expression to aggressive cellular behavior of OSCC was examined using in vitro cellular models wherein the expression of uPAR was manipulated and in a human OSCC tissue microarray. Results show altered adhesion, motility, and invasion in cells that overexpress uPAR relative to vector control cells. Distinct alterations of focal adhesion protein expression and phosphorylation, including p130cas and paxillin were observed, suggestive of enhanced focal adhesion turnover. Immunohistochemical analysis of microarrayed human OSCC revealed a significant correlation between uPAR and p130cas expression. The non-receptor protein tyrosine kinase c-Src was responsible for the phosphorylation of p130cas in response to uPAR/α3β1/laminin-5 engagement. Further downstream, the Rho family GTPase Cdc42, but not Rac1, was activated, suggesting a pathway leading to actin reorganization, filopodial protrusion and enhanced motility in uPAR overexpressing oral cancer cells. These data shed light on a molecular mechanism whereby acquisition of uPAR expression may modulate OSCC invasive activity through alteration of focal adhesion dynamics.
authors.affiliation: Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA. shiz@missouri.edu
authors.forename: Zonggao
authors.initials: Z
authors.lastname: Shi
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Johnson
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D040081:Protein Array Analysis; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D055293:Receptors, Urokinase Plasminogen Activator