Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/ijms222313006
Keywords
glioblastoma; MT1-MMP; EGCG; EMT; concanavalin A; SNAIL; STAT3
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2018-06651]
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This study investigated the expression of common EMT biomarkers induced by TGF-beta and MT1-MMP inducer ConA in human U87 glioblastoma cells through RNA-seq analysis and differential gene arrays. The findings highlight a new signaling axis linking MT1-MMP to TGF-beta-mediated EMT-like induction in glioblastoma cells.
Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-beta signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-beta signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-beta and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-beta triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-beta 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-beta-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-beta-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.
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