microRNA Expression Pattern Modulates Temozolomide Response in GBM Tumors with Cancer Stem Cells

Abstract

Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs.

Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

“… 8 , 103 , 104 , 105 , 106 , 107 Therefore, miRNAs can serve as potential targets for anti-GSC therapeutics. 103 , 108 , 109 , 110 …”

MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours

“…A multivariate analysis using paraffin-embedded (FFPE) ependymoma samples from patients has identified let-7d, miR-596, and miR-367 to be associated with increased overall survival [ 143 ]. These microRNAs are shown to regulate stem cells in other cancers like breast and brain [ 147 , 148 ]. Furthermore, miR-34a was shown to be overexpressed in supratentorial ependymomas which are associated with better prognosis in comparison to infratentorial tumours [ 143 ].…”

Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway

“…MiRNAs abnormally express in a variety of tumors and may have the effects of proto-oncogene or anti-oncogene (Stahlhut Espinosa and Slack, 2006). Accumulating researches showed that regulating the expression of miRNAs could enhance the benefits of chemotherapeutics in the treatment of tumors (Tezcan et al, 2014). Overexpressed miR-31 enhances the antitumor activity of TMZ in human GBM cells (Zhou et al, 2015).…”