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Angiogenesis, Metastasis, and the Cellular Microenvironment

A Suppressive Role of Mitogen Inducible Gene-2 in Mesenchymal Cancer Cell Invasion

¹ Department of Pathology and ² University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Chuanyue Wu, 707B Scaife Hall, Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: 412-648-2350; Fax: 509-561-4062. E-mail: carywu{at}pitt.edu

Cancer cell invasion of extracellular matrix (ECM) is essential for dissemination of cancer cells and metastasis. In this study, we have investigated the role of mitogen inducible gene-2 (Mig-2, also known as kindlin-2), a focal adhesion protein whose expression is altered in several types of human cancers, in mesenchymal cancer cell invasion. Mig-2 is abundantly expressed in SK-LMS-1 leiomyosarcoma cells. The level of Mig-2, however, is considerably lower in more invasive HT-1080 fibrosarcoma cells. Overexpression of Mig-2 in HT-1080 and SK-LMS-1 cells substantially reduced their ability to invade ECM in an in vitro Matrigel invasion assay. Conversely, knockdown of Mig-2 markedly increased the invasiveness of these cells. Consistent with a suppressive role in mesenchymal cancer cell invasion, Mig-2 inhibits urokinase-type plasminogen activator (uPA) secretion and pericellular proteolysis. Overexpression of Mig-2 increased uPA accumulation at the intracellular face of cell-ECM adhesions and reduced the level of secreted uPA. Conversely, knockdown of Mig-2 reduced uPA accumulation at the intracellular face of cell-ECM adhesions and increased uPA secretion. Our results reveal an important role of Mig-2 in suppression of mesenchymal cancer cell invasion and shed new light on how altered Mig-2 expression could influence cancer cell invasion. (Mol Cancer Res 2008;6(5):715–24)