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

Souad Djediai,Layal El Cheikh-Hussein,Sheraz Dhayne,Borhane Annabi,Zoé Joly-Lopez,Sahily Rodriguez Torres,Loraine Gresseau,Narjara Gonzalez Suarez

doi:10.3390/ijms222313006

Souad Djediai, Layal El Cheikh-Hussein + Show 6 more

Open Access

https://doi.org/10.3390/ijms222313006

Copy DOI

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.

Highlights

One of the compelling reasons that makes it difficult to foresee brain cancer therapy response relates to the adaptive metabolic mechanisms that regulate their chemoresistance phenotype [1,2]
Transforming growth factor (TGF)-β is a well-known contributor to epithelial-to-mesenchymal transition (EMT), and transforming growth factor (TGF)-β downstream signaling was found to be highly active in high-grade glioblastomas, the most fatal tumor of the central nervous system, where elevated TGF-β activity was associated with poor clinical outcome [4]
SNAIL among the Common EMT Biomarkers Induced by Concanavalin A and TGF-β in U87 Glioblastoma Cells

Summary

Introduction

One of the compelling reasons that makes it difficult to foresee brain cancer therapy response relates to the adaptive metabolic mechanisms that regulate their chemoresistance phenotype [1,2]. The tumor-promoting function of TGF-β is a promising potential therapeutic target in high-grade gliomas, including glioblastoma multiforme (GBM) [5]. Recent analysis of transcriptomic datasets about mesenchymal shift in GBM show that, in terms of epithelial and mesenchymal phenotype, the majority of GBM appear to have a transcriptomic profile that is more mesenchymal than epithelial [6]. If induced, this phenotype can be shifted toward an even more mesenchymal phenotype in an EMT-like process in glioma cells [7]. Studies have reported that TGF-β is able to induce metastatic processes and tumor progression via autocrine mechanisms [11,12]

Methods

Results

Discussion

Conclusion