Sakamoto Takeharu, Seiki Motoharu
Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Cancer Sci. 2017 Jun;108(6):1095-1100. doi: 10.1111/cas.13231. Epub 2017 May 22.
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.
膜型1基质金属蛋白酶（MT1-MMP）在包括癌细胞和基质细胞在内的不同类型的侵袭性和增殖性细胞中表达。MT1-MMP可切割细胞外基质蛋白、膜蛋白和其他细胞周围蛋白，从而改变细胞微环境并调节信号激活。许多研究小组已经证明了蛋白酶活性在癌细胞增殖、侵袭和转移中的关键作用。MT1-MMP还具有非蛋白酶活性，即它通过与Munc18-1相互作用蛋白3（Mint3）抑制缺氧诱导因子（HIFs）的氧依赖性抑制，从而增强HIF靶基因的表达。在表达MT1-MMP的癌细胞中，HIF活性升高是瓦伯格效应的一个基本机制，瓦伯格效应是一种众所周知的现象，即恶性癌细胞表现出更高的葡萄糖代谢率。由于MT1-MMP对HIF激活的特异性干预可抑制小鼠癌细胞的肿瘤形成，因此MT1-MMP的蛋白水解和非蛋白水解活性对于肿瘤恶性程度和功能的综合发挥都很重要。在这篇综述中，我们总结了有关MT1-MMP如何激活HIF及其对癌细胞和基质细胞影响的最新研究结果。
