Immunocytochemical staining for MMP-9 showed strong cytoplasmic immunoreactivity in the tumor cells and the proliferating endothelial cells of glioblastoma multiforme and anaplastic astrocytomas.
Our results also show that treatment of U87MG cells with the two isoflavones induced decreases in the enzymatic activity of MMP-9 and the protein levels of MT1-MMP and uPAR.
We characterized a high matrix metalloproteinase-9 (MMP-9) expressing U1242 MG intracranial xenograft mouse model that exhibited extensive individual cells and cell clusters in a perivascular and subpial cellular infiltrative pattern, geographic necrosis and infiltrating tumor-induced vascular proliferation closely resembling the human GBM phenotype.
The association of HSP27 with MMP-2 and MMP-9 proteins along with the identified interacting stretch has the potential to contribute towards drug development to inhibit GBM infiltration and migration.
In this study, we examined the role of ERK-1 in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which ERK1 is constitutively activated.
Luteolin treatment significantly inhibited glioblastoma cell migration, and this effect was associated with downregulated matrix metalloproteinase (MMP)-2, MMP-9 and upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.
In the current study, we examined the role of JNK- and ERK-dependent signaling modules in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which JNK/ERK1 is constitutively activated.
By Northern blot analysis we found increased levels of mRNAs encoding for gelatinase A, gelatinase B, two membrane-type MMPs (mt1- and mt2-MMP), and tissue inhibitors of metalloproteinase-1 in glioblastomas and medulloblastomas.
Downregulation of the miR-221/222 cluster diminished the invasion, migration, proliferation, and angiogenesis with reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, and vascular endothelial growth factor in glioblastoma cells.
These results demonstrate that miRNA-146a acts as a novel regulator to modulate the activity and transduction of TGF-β signaling pathways in glioblastoma, and the downregulation of miRNA-146a is required for overexpression of EGFR and MMP9, which can be considered an efficiently therapeutic target and a better understanding of glioblastoma pathogenesis.
Additionally, disruption of lipid rafts with methyl β cyclodextrin prevented Fas clustering and pU-Si-, pM-Si-, or pUM-Si-induced apoptosis, which is indicative of coclustering of Fas death receptor into lipid rafts in the glioblastoma xenograft cell lines 4910 and 5310.
Moreover, ATO significantly increased adhesion of U87MG cells and also diminished transcription of NF-κB down-stream targets involved in cell migration and invasion, including cathepsin B, uPA, MMP-2, MMP-9 and MMP-14 and suppressed proteolytic activity of cathepsin B, MMP-2 and MMP-9, demonstrating a possible mechanism of ATO effect on a well-known signaling in glioblastoma dissemination.
We profiled the immune-related gene set and identified 8 genes (FOXO3, IL6, IL10, ZBTB16, CCL18, AIMP1, FCGR2B, and MMP9) with the greatest prognostic value in GBM.
Immunohistochemistry demonstrated that gelatinase B was localized to vessel walls, to neutrophils in areas of hemorrhage, and in glioblastomas to macrophages.
Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment.
A significant decline of MMP-9 and MMP-2 secretion in cultured U87MG was detected after incubation with EBB (42.9% and 73.0%, respectively) and EBB + TMZ (38.4% and 68.5%, respectively).
Our results point out that the bicistronic construct, which can simultaneously silence both MMP-9 and uPAR offers a great therapeutic potential and is worth developing as a new drug for treating GBM patients.
Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI-3 K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote glioblastoma invasiveness.