MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1

Ariel Bier,Simona Cazacu,Amos Toren,Michal Yalon,Ana C Decarvalho,Elad Jacoby,Tom Mikkelsen,Noam Kronfeld,Cunli Xiang,Hae Kyung Lee,Chaya Brodie,Susan Finniss,Nis Giladi,Laila Poisson,Shimon Slavin

doi:10.18632/oncotarget.928

Ariel Bier, Simona Cazacu + Show 13 more

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https://doi.org/10.18632/oncotarget.928

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Abstract

Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.

Highlights

Glioblastoma (GBM), the most common and malignant primary brain tumors, are highly invasive, proliferative and vascularized [1]
We first examined the expression of miR-137 in GBM compared to normal brain specimens and in GSCs compared to neural stem cells (NSCs) using real-time PCR
We analyzed a region of CpG islands in miR137 promoter (Figure 1C) and found that this region is hypermethylated in GBM compared to normal brain specimens (Figure 1D)

Summary

Introduction

Glioblastoma (GBM), the most common and malignant primary brain tumors, are highly invasive, proliferative and vascularized [1]. The dismal prognosis of these patients is mainly due to the infiltrative nature of GBM and the resistance of residual tumor cells to current therapeutic modalities [4, 5]. GBM contain a small subpopulation of selfrenewing and tumorigenic cancer stem cells (glioma stem cells, GSCs) that are implicated in tumor infiltration, resistance to conventional therapies and tumor recurrence www.impactjournals.com/oncotarget. Understanding the mechanisms associated with the stemness and oncogenic features of these cells is essential for the development of therapeutic approaches that can eradicate GSCs and may provide the basis for the development of novel therapeutic approaches to treat GBM patients [6]. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either degradation or repression of mRNA translation [7, 8]. Alteration in miRNA expression has been associated with various disorders including cancer [9, 10]

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