Oral squamous cell carcinoma (SCC) is the most common cancer in head and neck with poor prognosis. However, the cellular and biochemical factors that underlie regional and distant spread of the disease are poorly understood. Invasion of OSCC requires multiple cellular events including dissolution of cell-cell junctions, basement membrane attachment, extracellular matrix proteolysis, and migration. We evaluated these properties in vitro using three OSCC lines (SNU-46, SNU-1066 and SNU-1076). Expression of adhesion molecules integrins as well as matrix degrading proteins were evaluated. Moreover, regulation of protease production by adhesion molecules was tested. Expression levels of the á3â1 integrin was high in SNU-1076 cells, moderate in SNU-1066 cells, and low in SNU-46 cells. á3â1 integrin clustering up-regulates expression of urinary-type plasminogen activator (uPA) in SNU-46 cells via a mechanism involving ERK activation. Both SNU-46 and SNU-1066 cells were responsive to á3â1 clustering, resulting in enhanced uPA expression. However, basal uPA levels were high in SNU-1076 cells and integrin clustering did not further stimulate uPA production. ERK was constitutively activated in SNU-1076 cells and treatment of cells with an inhibitor of ERK activation (PD98059) reduced uPA expression. Consistent with the enhanced proteolytic potential, SNU-1076 cells readily penetrated Matrigel and invasion was blocked by an anticatalytic uPA antibody. These data suggest that increased uPA production through integrin clusteringand ERK activation may play a important role in invasion of oral cancer, and alteration of adhesion-regulated proteinase production may lead to elevated pericellular proteinase activity, thereby contributing to the invasive potential of OSCC.