MT1-MMP Cooperates with TGF-β Receptor-Mediated Signaling to Trigger SNAIL and Induce Epithelial-to-Mesenchymal-like Transition in U87 Glioblastoma Cells

Abstract

Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-β signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-β signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-β and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-β receptor kinase inhibitor galunisertib, the JAK/STAT inhibitors AG490 and tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation, suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

“…SNAIL involvement in EMT has been well documented, and cancer therapeutic opportunities envisioned [ 42 ]. EGCG intervention against SNAIL-mediated EMT events was also recently addressed in U87 glioblastoma cells [ 43 ] and ES2 ovarian cancer cells [ 44 ].…”

EGCG Prevents the Onset of an Inflammatory and Cancer-Associated Adipocyte-like Phenotype in Adipose-Derived Mesenchymal Stem/Stromal Cells in Response to the Triple-Negative Breast Cancer Secretome

“…Once we identified the main upregulated genes and pathways involved in the acquisition of the CAA phenotype in ADMSC in response to the TNBC cells secretome, we investigated the impact of EGCG. This catechin is known to modulate molecular targets and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormone activities, detoxification enzymes, and immune response [ 50 , 51 , 52 , 53 , 54 ]. Our differential transcriptomic analysis performed in ADMSC treated in the presence or absence of EGCG revealed six times more modulated genes in samples treated with EGCG (92%, 8070 DEGs).…”

Effects of Epigallocatechin-3-Gallate on Matrix Metalloproteinases in Terms of Its Anticancer Activity

“…In U87 glioblastoma cells, chemotactic migration induced by TGF-β was suppressed by silencing either MT1-MMP or epithelial-mesenchymal transition-related protein SNAIL together with the reduced phosphorylation of decapentaplegic homolog (Smad)2/3 and STAT3 [ 103 ]. Similar results were observed by pharmacological inhibitors of STAT3 including EGCG, suggesting that EGCG’s suppression of MT1-MMT could lead to reduced migration of these cells.…”