The Expanding Role of MT1-MMP in Cancer Progression

Knapinska, Anna M.; Fields, Gregg B.

doi:10.3390/ph12020077

Cited by 51 publications

(48 citation statements)

References 145 publications

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“…These findings were consistent with those of a prior study which also found MMP‐14 overexpression to be related to tumor depth, clinical stage, lymph node metastasis, and vascular invasion in ESCC patients 16 . The upregulation of MMP‐14 has also been linked to poor prognosis in patients with bladder, breast, colorectal, lung, and ovarian cancers and with melanoma, advanced neuroblastoma, and tongue squamous cell carcinoma 4, 17, 18 . Together, these findings strongly suggest that MMP‐14 is a key regulator of tumor progression.…”

Section: Discussionsupporting

confidence: 91%

Matrix metalloproteinase‐14 (MMP‐14) downregulation inhibits esophageal squamous cell carcinoma cell migration, invasion, and proliferation

Chen

Zhang

et al. 2020

Thoracic Cancer

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Background Matrix metalloproteinase‐14 (MMP‐14) is known to be a key regulator of oncogenesis and tumor progression. The present study was designed to assess the relationship between the downregulation of MMP‐14 and the in vitro proliferative, migratory, and invasive activity of esophageal squamous cell carcinoma (ESCC) cells. Methods MMP‐14 expression in human ESCC and paracancerous normal esophageal tissue samples was evaluated via immunohistochemistry, and correlations between MMP‐14 staining and patient clinicopathological features were examined. In addition, siRNA was used to knockdown MMP‐14 in ESCC cells, and the proliferation and invasive activity of these cells were then evaluated via MTT and Transwell assays, respectively. Flow cytometry was additionally used to assess cell cycle progression, while Western blotting was employed to measure protein levels within these cells. Results ESCC samples were found to exhibit MMP‐14 overexpression relative to paracancerous tissue samples, and this overexpression was positively correlated with tumor T classification (T1‐2 vs. T3; P < 0.05), N classification (negative vs. positive; P < 0.001), degree of differentiation (G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05) and clinical stage (I–IIA vs. IIB–III; P < 0.05). When MMP‐14 was knocked down in ESCC cells, this induced cell cycle arrest, impairing their proliferative and invasive activity. Conclusions MMP‐14 is a key regulator of the proliferation and invasion of ESCC cells, making it a viable therapeutic target for the treatment of this cancer.

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Section: Discussionsupporting

confidence: 91%

Matrix metalloproteinase‐14 (MMP‐14) downregulation inhibits esophageal squamous cell carcinoma cell migration, invasion, and proliferation

Chen

Zhang

et al. 2020

Thoracic Cancer

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“…Next, we sought to investigate why ASCs are the cell population selectively expressing ΔDCN in WAT. Plasmalemma-bound MMP14 is known to cleave its substrates before they are secreted from the cell [ 47 ]. We therefore compared the MMP14 expression level in ASC to other cells.…”

Section: Resultsmentioning

confidence: 99%

“…This provides an explanation of how ΔDCN is generated in ASC. While cell surface-localized MMP14 cleaves many ECM substrates, intracellular cleavage by MMP14 has also been demonstrated [ 47 , 64 ]. The exact sub-cellular location where DCN cleavage by MMP14 occurs remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Glycosaminoglycan Modification of Decorin Depends on MMP14 Activity and Regulates Collagen Assembly

Daquinag

Gao

Fussell

et al. 2020

Cells

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Proper processing of collagens COL1 and COL6 is required for normal function of adipose tissue and skeletal muscle. Proteoglycan decorin (DCN) regulates collagen fiber formation. The amino-terminus of DCN is modified with an O-linked glycosaminoglycan (GAG), the function of which has remained unclear. Previously, non-glycanated DCN (ngDCN) was identified as a marker of adipose stromal cells. Here, we identify MMP14 as the metalloprotease that cleaves DCN to generate ngDCN. We demonstrate that mice ubiquitously lacking DCN GAG (ngDCN mice) have reduced matrix rigidity, enlarged adipocytes, fragile skin, as well as skeletal muscle hypotrophy, fibrosis, and dysfunction. Our results indicate that DCN deglycanation results in reduced intracellular DCN—collagen binding and increased production of truncated COL6 chains, leading to aberrant procollagen processing and extracellular localization. This study reveals that the GAG of DCN functions to regulate collagen assembly in adipose tissue and skeletal muscle and uncovers a new mechanism of matrix dysfunction in obesity and aging.

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“…The extracellular matrix (ECM) is an important substrate for tumor cell migration, but it also acts as a physical barrier whose degradation by matrix metalloproteinases (MMPs) is thought to be a critical step in tumor dissemination 9 – 11 . MMPs are a family of both transmembrane (designated “membrane-type” or “MT”) and secreted catalytic enzymes capable of cleaving ECM proteins and other substrates.…”

Section: Introductionmentioning

confidence: 99%

Coronin 1C inhibits melanoma metastasis through regulation of MT1-MMP-containing extracellular vesicle secretion

Tagliatela

Hempstead

Hibshman

et al. 2020

Sci Rep

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is overexpressed in multiple tumors, leading to the widely held view that this gene drives tumor progression, but this hypothesis has not been rigorously tested in melanoma. Here, we combined a conditional knockout of Coronin 1C with a genetically engineered mouse model of PTEN/ BRAF-driven melanoma. Loss of Coronin 1C in this model increases both primary tumor growth rates and distant metastases. Coronin 1C-null cells isolated from this model are more invasive in vitro and produce more metastatic lesions in orthotopic transplants than Coronin 1C-reexpressing cells due to the shedding of extracellular vesicles (EVs) containing MT1-MMP. Interestingly, these vesicles contain melanosome markers suggesting a melanoma-specific mechanism of EV release, regulated by Coronin 1C, that contributes to the high rates of metastasis in melanoma. Melanoma is the deadliest form of skin cancer with a high propensity for metastatic spread 1,2. The most common genetic drivers of melanoma are BRAF-activating mutations such as V600E, often found in conjunction with loss of tumor suppressors such as PTEN 3-5. If caught in its early stages, melanoma is treatable by surgical resection, but prognosis worsens significantly with the occurrence of in-transit, regional, or distant metastasis. Clinically, up to 54% of metastatic melanoma patients show tumor dissemination to the brain, 77% to the liver, and 85% to the lung 6. The high rate of metastasis in melanoma is poorly understood, but may be linked to lineage-specific factors that impact vesicular trafficking, secretion, degradation, and overall cell migration 7,8. The extracellular matrix (ECM) is an important substrate for tumor cell migration, but it also acts as a physical barrier whose degradation by matrix metalloproteinases (MMPs) is thought to be a critical step in tumor dissemination 9-11. MMPs are a family of both transmembrane (designated "membrane-type" or "MT") and secreted catalytic enzymes capable of cleaving ECM proteins and other substrates. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a particularly important pro-invasive MMP across many cancer types 12 and whose expression closely correlates with invasion and metastasis 13-15. MT1-MMP is also unique in its ability to both directly cleave a wide range of ECM proteins including collagen types I, II, and III, laminin 1 and 5, and fibronectin, as well as activate pro-MMP2 16. The trafficking of MT1-MMP to and from the plasma membrane (PM) and other membrane structures is surprisingly complex, but critical for the protein's function during tumor invasion and metastasis. Phosphorylation of the cytoplasmic tail initiates internalization of MT1-MMP from the PM by both clathrin-mediated and caveolin-mediated routes 13. Internalized vesicles traffic through the endolysosomal pathway, resulting in redirection to other areas of the PM or to the lysosome for degradation 17. MT1-MMP recycling has been shown to involve various flotilins 18 and SNARE proteins 19-22 , as well as a variety of Rab proteins including Rab5, Rab7 1...

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The Expanding Role of MT1-MMP in Cancer Progression

Cited by 51 publications

References 145 publications

Matrix metalloproteinase‐14 (MMP‐14) downregulation inhibits esophageal squamous cell carcinoma cell migration, invasion, and proliferation

Matrix metalloproteinase‐14 (MMP‐14) downregulation inhibits esophageal squamous cell carcinoma cell migration, invasion, and proliferation

Glycosaminoglycan Modification of Decorin Depends on MMP14 Activity and Regulates Collagen Assembly

Coronin 1C inhibits melanoma metastasis through regulation of MT1-MMP-containing extracellular vesicle secretion

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