Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase.
Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase.
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DOI：
10.1111/cas.13231
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发表时间：
2017-06
期刊：
影响因子：
5.7
通讯作者：
Seiki M
中科院分区：
文献类型：
--
作者：
Sakamoto T;Seiki M
膜型1基质金属蛋白酶（MT 1-MMP）在不同类型的侵袭性和增殖性细胞中表达，包括癌细胞和基质细胞。MT 1-MMP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。蛋白酶活性在癌细胞增殖、侵袭和转移中的关键作用已被许多研究小组证实。MT 1-MMP还具有非蛋白酶活性，因为它通过Munc 18 - 1相互作用蛋白3（Mint 3）抑制缺氧诱导因子（HIF）的氧依赖性抑制，从而增强HIF靶基因的表达。表达MT 1-MMP-的癌细胞中HIF活性升高是瓦尔堡效应的基本机制，沃伯格效应是一种众所周知的现象，恶性癌细胞表现出更高的葡萄糖代谢率。由于MT 1-MMP对HIF激活的特异性干预抑制了小鼠癌细胞的肿瘤形成，因此MT 1-MMP的蛋白水解和非蛋白水解活性对肿瘤恶性程度和功能都很重要。在这篇综述中，我们总结了有关MT 1-MMP如何激活HIF及其对癌细胞和基质细胞的影响的最新研究结果。
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.