Open AccessIntegrated functions of membrane‐type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase
Author(s) -
Sakamoto Takeharu,
Seiki Motoharu
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13231
Subject(s) - cancer cell , stromal cell , matrix metalloproteinase , extracellular matrix , tumor microenvironment , microbiology and biotechnology , cancer , metastasis , metalloproteinase , biology , chemistry , cancer research , biochemistry , genetics
Membrane‐type 1 matrix metalloproteinase ( MT 1‐ MMP ) is expressed in different types of invasive and proliferative cells, including cancer cells and stromal cells. MT 1‐ 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. MT 1‐ MMP also has a non‐protease activity in that it inhibits the oxygen‐dependent suppression of hypoxia‐inducible factors ( HIF s) via Munc18‐1‐interacting protein 3 (Mint3) and thereby enhances the expression of HIF target genes. Elevated HIF activity in MT 1‐ 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 MT 1‐ MMP suppresses tumor formation by cancer cells in mice, both the proteolytic and non‐proteolytic activities of MT 1‐ MMP are important for tumor malignancy and function in an integrated manner. In this review, we summarize recent findings relating to how MT 1‐ MMP activates HIF and its effects on cancer cells and stromal cells.