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Glioblastoma is the most aggressive form of brain tumor originating from glial cells with a maximum life expectancy of 14.6 months. Despite the establishment of multiple promising therapies, the clinical outcome of glioblastoma patients is abysmal. Drug resistance has been identified as a major factor contributing to the failure of current multimodal therapy. Epigenetic modification, especially DNA methylation has been identified as a major regulatory mechanism behind glioblastoma progression. In addition, miRNAs, a class of non-coding RNA, have been found to play a role in the regulation as well as in the diagnosis of glioblastoma. The relationship between epigenetics, drug resistance, and glioblastoma progression has been clearly demonstrated. MGMT hypermethylation, leading to a lack of MGMT expression, is associated with a cytotoxic effect of TMZ in GBM, while resistance to TMZ frequently appears in MGMT non-methylated GBM.
miRNAs are regulators of the pathways that play crucial roles in GBM invasion and progression. Their expression predicts the efficacy of conventional therapies that are routinely used in GBM treatment [26]. Most miRNAs have already been reported to be dysregulated in GBM so far. Therefore, miRNAs are currently being considered as potential diagnostic and prognostic biomarkers of gliomas [54]. Several studies have validated the potential roles of circulating miRNAs, particularly found in body fluids, such as CSF, plasma, and serum, in GBM diagnosis.
miR-21 is a potential biomarker of GBM with 90% sensitivity and 100% specificity [55]. It has been observed to have low expression in the post-operation serum of GBM patients, suggesting its potential as a serum-derived miRNA biomarker in GBM [33].
miR-26a and miR-21 are both circulatory miRNAs that are upregulated in GBM, and their serum expression levels have been observed to be reduced after surgery [33], suggesting their importance as candidate serum-based biomarkers in the diagnosis of GBM as well as in monitoring disease progression [33].
miR-10b is upregulated in GBM, and its overexpression promotes GBM progression and correlates with poor prognosis [55]. Its expression level positively correlates with WHO grades of gliomas as well as with tumor invasiveness [24]. Therefore, miR-10b might be used as a biomarker to evaluate glioma invasiveness and, subsequently, in the sub-classification of different tumor grades.
miR-328 is downregulated in GBM and acts as a tumor suppressor. The low expression level of miR-328 correlates with poor survival rate, thus it might be used as a candidate prognostic biomarker in GBM [45].
High plasma levels of miR-21 and low plasma levels of miR-128 and miR-342-3p act as candidate biomarkers in distinguishing GBM patients from healthy individuals with remarkably high sensitivity and specificity [56]. miR-342-3p expression is reduced in the plasma of glioma patients, and it is increased after surgery or chemotherapy.
miR-320a is a tumor suppressor miRNA, and its suppression correlates with excessive cell proliferation, invasion, and tumor growth [27]. Therefore, it might be used as a prognostic biomarker [27]. miR-146b and miR-4492 can be useful as novel biomarkers in predicting and monitoring GBM progression [27]. miR-146b is an oncogenic miRNA, and its major target is TRAF6. Downregulation of miR-146b and upregulation of TRAF6 correlate with inhibition of cell proliferation as well as apoptosis of tumor cells due to a decrease in Ki-67 expression.
miR-29 plasma level serves as a potential biomarker to indicate malignancy and glioma progression from grades I-II to grades III-IV [57]. miR-454-3p serum expression levels have been found markedly increased in GBM patients, and its upregulation correlates with poor prognosis.
Sometimes, single miRNA profiling is not sufficient enough to predict glioma outcomes. In such cases, profiles of several miRNAs are suggested. Seven miRNAs, including miR-15b, miR-23a, miR-133a, miR-150, miR-197, miR-497, and miR-548b-5p, are all downregulated in grades II-IV glioma patients, and the combined expression profiling of these miRNAs might be taken as a candidate biomarker in the prediction of GBM malignancy [57].
miR-181 is widely reported to be downregulated in GBM, especially in the early stages of this tumor [57]. Therefore, miR-181 might be used as a candidate biomarker for early prediction as well as in the identification of tumor grade. miR-181b and miR-181c act as predictive biomarkers of TMZ response in GBM [57] and may also help in choosing patients who are suitable for adjuvant therapy [26].
miR-221/222 is found to be significantly upregulated in plasma samples of glioma patients [26][58], and its overexpression contributes to poor prognosis and low survival rates [58].