title: Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase.
abstract: Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed in different types of invasive and proliferative cells, including cancer cells and stromal cells. MT1-MMP cleaves extracellular matrix proteins, membrane proteins and other pericellular proteins, thereby changing the cellular microenvironment and regulating signal activation. Critical roles of protease activity in cancer cell proliferation, invasion and metastasis have been demonstrated by many groups. MT1-MMP also has a non-protease activity in that it inhibits the oxygen-dependent suppression of hypoxia-inducible factors (HIFs) via Munc18-1-interacting protein 3 (Mint3) and thereby enhances the expression of HIF target genes. Elevated HIF activity in MT1-MMP-expressing cancer cells is a fundamental mechanism underlying the Warburg effect, a well-known phenomenon where malignant cancer cells exhibit a higher rate of glucose metabolism. Because specific intervention of HIF activation by MT1-MMP suppresses tumor formation by cancer cells in mice, both the proteolytic and non-proteolytic activities of MT1-MMP are important for tumor malignancy and function in an integrated manner. In this review, we summarize recent findings relating to how MT1-MMP activates HIF and its effects on cancer cells and stromal cells.
authors.affiliation: Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeharu
authors.identifier: http://orcid.org/0000-0002-1225-1902
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D010447:Peptide Hydrolases; D053511:Matrix Metalloproteinase 14
keywords: Cancer; MT1-MMP; hypoxia; signal transduction; tumor microenvironment