Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling - 11/07/18
pages | 12 |
Iconographies | 9 |
Vidéos | 0 |
Autres | 0 |
Graphical abstract |
Highlights |
• | TF-FVIIa or Trypsin induces MMP-2 expression in human breast cancer cells. |
• | TF-FVIIa or Trypsin-induced MMP-2 expression is dependent on PAR2. |
• | PAR2-dependent MMP-2 expression is mediated by AKT/NF-ĸB activation. |
• | MMP-2 promotes cell invasion and migration in an autocrine manner. |
• | P38 MAPK, MK2 and HSP27 activation is essential in MMP-2-induced cell migration. |
Abstract |
Aims |
Cell invasion is attributed to the synthesis and secretion of proteolytically active matrix-metalloproteinases (MMPs) by tumor cells to degrade extracellular matrix (ECM) and promote metastasis. The role of protease-activated receptor 2 (PAR2) in human breast cancer migration/invasion via MMP-2 up-regulation remains ill-defined; hence we investigated whether TF-FVIIa/trypsin-mediated PAR2 activation induces MMP-2 expression in human breast cancer.
Main methods |
MMP-2 expression and the signaling mechanisms were analyzed by western blotting and RT-PCR. MMP-2 activity was measured by gelatin zymography. Cell invasion was analyzed by transwell invasion assay whereas; wound healing assay was performed to understand the cell migratory potential.
Key findings |
Here, we highlight that TF-FVIIa/trypsin-mediated PAR2 activation leads to enhanced MMP-2 expression in human breast cancer cells contributing to tumor progression. Knock-down of PAR2 abrogated TF-FVIIa/trypsin-induced up-regulation of MMP-2. Again, genetic manipulation of AKT or inhibition of NF-ĸB suggested that PAR2-mediated enhanced MMP-2 expression is dependent on the PI3K-AKT-NF-ĸB pathway. We also reveal that TF, PAR2, and MMP-2 are over-expressed in invasive breast carcinoma tissues as compared to normal. Knock-down of MMP-2 significantly impeded TF-FVIIa/trypsin-induced cell invasion. Further, we report that MMP-2 activates p38 MAPK-MK2-HSP27 signaling axis that leads to actin polymerization and induces cell migration. Pharmacological inhibition of p38 MAPK or MK2 attenuates MMP-2-induced cell migration.
Significance |
The study delineates a novel signaling pathway by which PAR2-induced MMP-2 expression regulates human breast cancer cell migration/invasion. Understanding these mechanistic details will certainly help to identify crucial targets for therapeutic interventions in breast cancer metastasis.
Le texte complet de cet article est disponible en PDF.Abbreviations : PAR2, TF, FVIIa, MMP-2, rMMP-2, HSP27, RT-PCR, NF-ĸBI
Keywords : Tissue factor, Factor VIIa, Protease activated receptor 2, Matrix metalloproteinase-2, Breast cancer metastasis
Plan
Vol 105
P. 395-406 - septembre 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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