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

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.

Long Non-Coding RNA SNHG6 Supports Glioma Progression Through Upregulation of Notch1, Sox2, and EMT

Gliomas, particularly the advanced grade glioblastomas, have poor 5-year survival rates and worse outcomes. lncRNAs and EMT have been extensively studied in gliomas but the disease progression remains poorly understood. SNHG6 has been shown to affect glioma cell proliferation but its effect on EMT of glioma cells along with its effect on disease progression is not known. We screened four glioma cell lines; H4, A172, U87MG, and SW088 and grouped them based on high vs. low SNHG6 expression. Transfections with SNHG6 specific siRNA resulted in induction of apoptosis of high SNHG6 expressing A172 and U87MG cells. This was accompanied by inhibition of EMT and downregulation of EMT-modulating factor Notch1, β-catenin activity and the cancer stem cell marker Sox2. The regulation was not found to be reciprocal as silencing of Notch1 and Sox2 failed to affect SNHG6 levels. The levels of SNHG6 and Notch1 were also found elevated in Grade IV glioma patients (n = 4) relative to Grade II glioma patients (n = 5). These results identify SNHG6 and Notch1 as valid targets for glioma therapy.