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

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.

Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Malignant Neoplasms of the Brain in Taiwan

“…MSI1 causes tumor migration by binding with ICAM1 RNA, leading to poor prognosis [ 24 ]. MSI1 can be inhibited by microRNAs to reduce brain carcinogenesis [ 25 ]. RBFOX1 could not be confirmed based on previous studies to have positive or negative correlations with gliomagenesis.…”

Shedding light on function of long non-coding RNAs (lncRNAs) in glioblastoma

“…The stimulation of glucose metabolism by PKM2 can reinforce the antioxidant defense system in the development of radio-resistance in GBM [ 145 ]. miRNA-671–5p undergoes down-regulation by MSI1 in GBM and it can mediate CSC features and metastasis of tumor cells [ 146 ]. Noteworthy, miRNA-671–5p down-regulation results in activation of STAT3 and TRAF2 as two downstream targets to mediate radio-resistance in GBM cells [ 146 ].…”

“…miRNA-671–5p undergoes down-regulation by MSI1 in GBM and it can mediate CSC features and metastasis of tumor cells [ 146 ]. Noteworthy, miRNA-671–5p down-regulation results in activation of STAT3 and TRAF2 as two downstream targets to mediate radio-resistance in GBM cells [ 146 ]. The nuclear translocation of Rad51 can mediate radio-resistance in GBM cells.…”

Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies

“…RBP can regulate the modification and translation of mRNA and affect the processing of miRNA and circRNA, playing a key role in cancer progression and metastasis [114]. Musashi-1 (MSI1), as a RBP and a CSC biomarker, can increase downstream RNA stability and interact with miRNA, thereby altering the expression and activity of OCT4 and STAT3 [115,116]. Studies have shown that RBP La stimulates the post-transcriptional expression of TF ZEB1 and mediates TGF-β Induced EMT and stemness of CSCs [117].…”