부산대학교 도서관

Metastatic melanoma remains the deadliest of all skin cancers with a survival rate at five years of less than 15%. MT1- MMP is a membrane-associated matrix metalloproteinase that controls pericellular proteolysis and is an important, invasion-promoting, pro-tumorigenic MMP in cancer. We show that deregulation of MT1- MMP expression happens as early as the transition from nevus to primary melanoma and continues to increase during melanoma progression. Furthermore, MT1- MMP expression is associated with poor melanoma patient outcome, underscoring a pivotal role of MT1- MMP in melanoma pathogenesis. We demonstrate that MT1- MMP is directly required for melanoma cells to metastasize, as cells deprived of MT1- MMP fail to form distant metastasis in an orthotopic mouse melanoma model. We show that MT1- MMP affects cell invasion by activating its target MMP2. Importantly, we demonstrate, for the first time, that activation of MMP2 by MT1- MMP is required to sustain RAC1 activity and promote MT1- MMP-dependent cell motility. These data highlight a novel MT1- MMP/ MMP2/ RAC1 signaling axis in melanoma that may represent an intriguing molecular target for the treatment of invasive melanoma. [ABSTRACT FROM AUTHOR]