miR-124-mediated temozolomide sensitivity and DNA repair modulation in Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is the most frequent and invasive primary malignant brain tumor. One approach to improve the effectiveness of GBM treatment is the combination of miRNA-targeted therapy with TMZ. This study aimed to assess the effect of miR-124 overexpression on TMZ resistance in GBM cell lines. Additionally, we examined how miR-124 overexpression affects the expression of genes involved in DNA repair processes. We conducted a bioinformatics prediction for target genes of miR‑124‑3p and then overexpressed miR-124 in U-87 and U-251 cell lines through lentiviral transduction. Sixty genes were identified as potential targets of miR-124-3p, which revealed overlap among 504 target mRNAs and upregulated genes across four GEO datasets. PRRX1, ETS, VIM, and PTBP1 genes were selected based on their contributions to DNA repair and related processes such as autophagy including Beclin-1 and Atg-5. The MTT assay results showed that only the U87 cell line overexpressing miR-124 exhibited significantly greater sensitivity to TMZ treatment. The qRT-PCR analysis revealed a significant reduction in mRNA levels of all DNA repair-related genes and two autophagy-related genes in both cell lines. The results might indicate that after TMZ-induced genomic damage, cells activate the DNA repair pathways, ultimately leading to the development of resistance. In the context of TMZ treatment, autophagy is considered a protective process for cancer cells, and definitive proof of its association with the anti-cancer activity of miR-124 requires further supplementary tests. So, modulating DNA repair pathways with miR-124 could enhance the chemosensitivity of Glioma cells to TMZ.