Transforming Growth Factor-Beta-Regulated LncRNA-MUF Promotes Invasion by Modulating the miR-34a Snail1 Axis in Glioblastoma Multiforme.

Bakhya Shree,Vivek Sharma,Shraddha Tripathi

doi:10.3389/fonc.2021.788755

Abstract

Transforming growth factor beta (TGF-β)-regulated long-non-coding RNAs (lncRNAs) modulate several aspects of tumor development such as proliferation, invasion, metastasis, epithelial to mesenchymal transition (EMT), and drug resistance in various cancers, including Glioblastoma multiforme (GBM). We identified several novel differentially expressed lncRNAs upon TGF-β treatment in glioma cells using genome-wide microarray screening. We show that TGF-β induces lncRNA-MUF in glioma cells, and its expression is significantly upregulated in glioma tissues and is associated with poor overall survival of GBM patients. Knockdown of lncRNA-MUF reduces proliferation, migration, and invasion in glioma cells and sensitizes them to temozolomide (TMZ)-induced apoptosis. In addition, lncRNA-MUF downregulation impairs TGF-β-induced smad2/3 phosphorylation. In line with its role in regulating invasion, lncRNA-MUF functions as a competing endogenous RNA (ceRNA) for miR-34a and promotes Snail1 expression. Collectively, our findings suggest lncRNA-MUF as an attractive therapeutic target for GBM.

Highlights

Glioblastoma multiforme (GBM) is a heterogeneous malignancy of the central nervous system characterized by aggressive invasion into the surrounding tissue [1]
LncRNAs constitute 18.3% of transcripts among the total number of differentially expressed genes (DEGs) identified upon TGF-b1 treatment in T98G cells (Figure 1B)
To further identify the genes regulated in trans by long-non-coding RNAs (lncRNAs)-MUF in glioma cells, we evaluated the expression of the Transforming growth factor beta (TGF-b) gene ontology group upon its siRNA-mediated knockdown

Summary

Introduction

GBM is a heterogeneous malignancy of the central nervous system characterized by aggressive invasion into the surrounding tissue [1]. One of the characteristic features of GBM is extensive infiltration and invasion of the tumor cells to the surrounding parenchyma, which leads to colonization and relapse of tumors [3]. TGF-b is a cytokine with multiple functions regulating cell proliferation, differentiation, and tissue homeostasis [4, 5]. TGF-b promotes cancer cell invasion, EMT, and chemoresistance [5]. TGF-b is overexpressed in glioblastoma, and its elevated expression is associated with the increased histologic grade of GBM [6]. TGF-b promotes proliferation, invasion, metastasis, angiogenesis, resistance to apoptosis, replicative immortality, evasion of growth suppression, evasion of immune checkpoint blockade, and chemoresistance in GBM [7,8,9]

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Results

Conclusion