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

Abstract

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.