MiR-671-5p Inhibition by MSI1 Promotes Glioblastoma Tumorigenesis via Radioresistance, Tumor Motility and Cancer Stem-like Cell Properties.

Jang-Chun Lin,Wei-Hsiu Liu,Chun-Yuan Kuo,Jo-Ting Tsai

doi:10.3390/biomedicines10010021

Abstract

MicroRNAs (miRNAs) could be potential biomarkers for glioblastoma multiforme (GBM) prognosis and response to therapeutic agents. We previously demonstrated that the cancer stem cell marker Musashi-1 (MSI1) is an RNA binding protein that promotes radioresistance by increasing downstream RNA stability. To identify that MSI1 interacts with miRNAs and attenuates their function, we also get candidate miRNAs from the mRNA seq by predicting with TargetScan software. miR-671-5p in GBM cells interacts with MSI1 by intersecting the precipitated miRNAs with the predicted miRNAs. Notably, overexpression of MSI1 reversed the inhibitory effect of miR-671-5p. The phenotype of miR-671-5p in GBM cells could affect radiosensitivity by modulating the posttranscriptional activity of STAT3. In addition, miR-671-5p could attenuate tumor migration and cancer stem cell (CSC) characteristics by repressing the posttranscriptional activity of TRAF2. MSI1 may regulate GBM radioresistance, CSCs and tumor motility through miR-671-5p inhibition to increasing STAT3 and TRAF2 presentation. In vivo, the GBM tumor size was inversely correlated with miR-671-5p expression, but tumorigenesis was promoted by STAT3 and TRAF2 activation in the miR-671-5p-positive GBM population. miR-671-5p could be activated as a novel therapeutic target for GBM and has potential application as a predictive biomarker of glioblastoma prognosis.

Highlights

The most lethal primary malignancy in adults is glioblastoma multiforme (GBM)
Musashi-1 (MSI1) is an RNA binding protein (RBP). It is a well-known neural stem cell marker and a factor of radioresistance that acts by enhancing homologous recombination repair, cancer stem cell-like properties and tumor motility in GBM [3]
It is estimated that miRNAs can regulate up to 60% of human genes, including genes associated with maintaining the stem-like phenotype, differentiation, and chemo- and radioresistance [25–27]

Summary

Introduction

The most lethal primary malignancy in adults is glioblastoma multiforme (GBM). Despite multimodal treatments consisting of surgical intervention and adjuvant concomitant chemoradiotherapy, the prognosis remains dismal [1]. Musashi-1 (MSI1) is an RNA binding protein (RBP) It is a well-known neural stem cell marker and a factor of radioresistance that acts by enhancing homologous recombination repair, cancer stem cell-like properties and tumor motility in GBM [3]. LncRNAs exist to promote and to suppress GBM progression through cross-regulation of miRNAs. For example, CASC9 (a kind of lncRNA), miR-519d, and STAT3 make a positive circle to activate glioma carcinomgenesis [7]. MicroRNAs (miRNAs) are a group of short noncoding RNAs (~20–22 nucleotides) that regulate gene expression by binding to the 30 -untranslated region (30 UTR) of target mRNAs [9]. They usually negatively regulate target genes by direct interaction with the 30 UTR [10]. Our data indicate that the molecular mechanisms of glioblastoma tumorigenesis suggest potential therapeutic targets and prognostic markers

Materials and Methods

Results

Activation of the MSI1/miR-671-5p/STAT3 Axis Regulates Radiosensitivity

The MSI1/miR-671-5p/TRAF2 Axis Mediates EMT and CSC Abilities

Findings

Discussion