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Hasan, H.; Afzal, M.; Castresana, J.S.; Shahi, M.H. Epigenetic Effects of miRNAs in Glioblastoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/46962 (accessed on 24 June 2024).
Hasan H, Afzal M, Castresana JS, Shahi MH. Epigenetic Effects of miRNAs in Glioblastoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/46962. Accessed June 24, 2024.
Hasan, Hera, Mohammad Afzal, Javier S. Castresana, Mehdi H. Shahi. "Epigenetic Effects of miRNAs in Glioblastoma" Encyclopedia, https://encyclopedia.pub/entry/46962 (accessed June 24, 2024).
Hasan, H., Afzal, M., Castresana, J.S., & Shahi, M.H. (2023, July 19). Epigenetic Effects of miRNAs in Glioblastoma. In Encyclopedia. https://encyclopedia.pub/entry/46962
Hasan, Hera, et al. "Epigenetic Effects of miRNAs in Glioblastoma." Encyclopedia. Web. 19 July, 2023.
Epigenetic Effects of miRNAs in Glioblastoma
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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. 

glioblastoma miRNA temozolomide epigenetics

1. The CNS5 Classification and Glioblastoma

Glioblastoma, according to the 2021 WHO (World Health Organization) Classification of Tumors of the Central Nervous System, or CNS5 classification [1], is an IDH wild-type glioma. Previous classifications considered glioblastoma as primary (IDH wild type) and secondary (IDH mutant) [2]. CNS5 classification has simplified the subdivisions of adult-type diffuse gliomas, dividing them into three tumor types: astrocytoma (IDH mutant), oligodendroglioma (IDH mutant and 1p/19q codeletion), and glioblastoma (IDH wild type).
Glioblastoma, according to the CNS5 classification, is defined as a diffuse astrocytic WHO grade 4 glioma, IDH wild type, and H3 wild type, that has one or more of the following histological or genetic features: microvascular proliferation, necrosis, TERT promoter mutation, EGFR amplification, and +7/−10 chromosome and copy-number changes at chromosomes 7 (gains and amplifications) and 10 (losses) [1][2].
Despite the availability of a plethora of aggressive treatments and conventional therapies, such as chemotherapy, radiotherapy, and surgical resection, glioblastoma (GBM) is still irremediable, obnoxiously fatal, and almost invariably leads to patient death. GBM stem cells (GSCs) constitute a subpopulation of GBM cells that contribute to the failure of conventional treatments, as they are highly tumorigenic but relatively quiescent cells, which make them resistant to conventional therapies [3]. Some idiosyncrasies of GBM have been identified, which make GBM a very particular entity, separated from the rest of gliomas. GBM exhibit central necrosis and microvascular proliferation, are highly infiltrative, and rarely display extracranial metastases; they are exceptionally invasive, and their rate of migration is so high that they are spread far away from their origin and even extend across the contralateral brain hemisphere, making complete surgical resection of GBM achingly complicated. GBM is highly vascularized and presents a high mutation rate and significant genetic instability that contributes to intra-tumor heterogeneity, which complicates therapy [4].
Epigenetics is broadly defined as the study of heritable aberrations in gene expression without any change in DNA sequence [5]. Moreover, the reversible nature of epigenetic modification has engendered an endeavor to develop more progressive novel therapeutic approaches aiming to combat GBM [6]. Epigenetic modification plays a critical role in the transformation of normal to malignant cells via a complex interplay with genetic alterations, impacting critical cellular processes involved in the progression of glioma, such as DNA repair, apoptosis, and cell invasion and proliferation, which profoundly contribute to the catastrophic disruption of normal cells, transforming them to high-grade glioma cells [7].
MicroRNAs (miRNAs) are small non-coding endogenous RNAs, typically 21 to 23 nucleotides long. They exert their regulatory effect post-transcriptionally by regulating a large number of genes through silencing the expression of specific mRNAs, a process called RNA interference (RNAi). Additionally, miRNAs can regulate the expression of a plethora of genes that play a key role in cancer. For example, EZH2, a chromatin modifier, has been reported to be regulated directly by miR-205, mRNA-101, and miR-26a [8]. miRNAs play crucial roles in GBM progression either by acting as oncogenic miRNAs via silencing tumor suppressor genes or by acting as tumor suppressors.

2. DNA Methylation

DNA methylation is a type of epigenetic modification that plays a key role in the regulation of chromatin structure, genome imprinting, and gene expression [9]. Most studies based on DNA methylation as an epigenetic mark predominantly focuses on methylation of a cytosine residue followed by a guanine, a reaction in which a methyl group is covalently transferred to the 5′-position of cytosine, forming 5-methyl cytosine (5mC), which occurs via an enzyme called DNA methyl transferase (DNMT) [7]. DNMT family consists of 5 members: DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L [7]. Among them, DNMT1 specifically targets hemi-methylated DNA, while DNMT3a and DNMT3b are involved in the de novo methylation of unmethylated substrates [6][7].
DNA methylation usually inhibits the transcription of eukaryotic genes, particularly when it occurs in their promoters. DNMTs transfer methyl residues from SAM (S-adenosyl methionine) to DNA, thus preventing the binding of transcription factors to the promoter region of target genes. DNA methylation usually targets CpG islands, which are clusters of CpG dinucleotides that are found in the promoter regions in nearly half of all human genes [7]. CpG islands are genomic regions of 200 base pairs with a 50% GC content of total nucleotides and a CpG ratio > 0.6 [9]. CpG islands are hypomethylated under standard physiological conditions [6], which correlates with active gene expression, whereas CpG islands of tumor cells have been found to be hypermethylated in DNA repair genes and tumor suppressor genes involved in cell proliferation and progression, which results in transcriptional silencing of these genes [6].

2.1. DNA Methylation in GBM

Cancer-specific DNA methylation is characterized by the global loss of methylation accompanied by gene promoter hypermethylation. Specific CpG hypermethylation of tumor suppressor gene promoters resulting in transcriptional silencing is the most widely studied epigenetic aberration in GBM [7][10]. While hypomethylation takes place in the repetitive region of the DNA that might be responsible for genomic instability contributing to tumor growth [7], hypermethylation of the MGMT (O6-methylguanine-DNA methyltransferase) promoter leads to MGMT epigenetic silencing in about 40% of GBM, which correlates with a better response to temozolomide (TMZ) treatment with an increase in median survival time [7][9].

2.2. DNA Methylation: Its Role in Regulation of Metabolism in GBM

DNA methylation has been reported to be involved in the modification of genes related to glycolysis in GBM. DNA-methylating enzymes exert their regulatory effect on metabolic target genes, either via methylating DNA in introns or in the promoter region, thus silencing the expression of these genes.

2.3. PKM2

This enzyme controls the synthesis of pyruvate, the last metabolite of the glycolytic pathway. Hypomethylation at intron 1 of the PKM gene has been observed to exhibit a positive correlation with GBM. Additionally, PKM2 is under the regulation of miR-7, miR-326, and Let miR-7. Hence, PKM2 might be a useful target for several cancer-suppressing drugs [11].

2.4. LDHA

LDHA gene codes for lactate dehydrogenase, a glycolytic enzyme. Epigenetic silencing of this gene via hypermethylation of their promoter region has been documented in IDH-mutant GBM, according to classifications previous to CNS5 [11][12].

2.5. HK2

HK2 gene codes for hexokinase that catalyzes the rate-limiting step of glycolysis: phosphorylating glucose to glucose-6-phosphate. Aberration in the methylation status of this gene either via hypermethylation or hypomethylation of CpG islands within intron 1 has been reported in GBM cell lines or tumors [11]. Predominantly, hypomethylation has been found to be a frequent event in GBM compared to normal cells [11][13]. Several studies authenticate the HK2 overexpression contribution to tumor growth with a drug-resistant phenotype [13].

3. miRNA

MicroRNAs (miRNAs/miRs) are small non-coding RNAs of 19–22 nucleotides long [14][15] profoundly involved in post-transcriptional regulation of expression of a plenitude of genes either via sequence-specific repression of mRNA [14] or mRNA degradation. The first miRNA was discovered in Caenorhabditis elegans in 1993 [16]. miRNAs play a pivotal role as modulators of cellular homeostasis and regulate several major cellular processes, such as proliferation, migration, cell cycle progression, and apoptosis [16][17]. Dysregulation of miRNA unequivocally has been associated with a wide range of clinical conditions, such as cancer, neurodegenerative diseases, and cardiovascular diseases.

3.1. miRNA Biogenesis

miRNA biogenesis can progress through two pathways: canonical and non-canonical. Among them, the canonical pathway is the most important one related to miRNA biogenesis and maturation [18]. The first step of the canonical pathway concerns the synthesis of pri-miRNA from the genome by the enzyme RNA polymerase III/II followed by its subsequent cleavage into pre-miRNA through a microprocessor complex consisting of Drosha-DGCR8 complex [16][18][19]. Drosha is a nuclear RNase III enzyme that cleaves hairpin loop sequences in pri-miRNA [19], resulting in the production of ~70 nucleotides (nt) pre-miRNA bearing a 2 nt 3′ overhang [18]. After the completion of these initial steps in the nucleus, pre-miRNA is shuttled out of the nucleus into the cytoplasm by a nuclear transporter protein Ran/GTP/Exportin-5 (XPO5) for final processing via Dicer enzyme and TARBP2 [20][21]. Dicer is an RNAase III endonuclease that cleaves a pre-miRNA into a mature miRNA duplex [20]. The final step that marks the end of miRNA biogenesis is a load of either the 3p or 5p strand of the mature miRNA duplex, depending on their thermodynamic stability, into the Argonaute (AGO) protein, making functional miRISC (miRNA-induced silencing complex) [18] recognize the 3′-UTR of a target gene and result in translational suppression or degradation of mRNA via a phenomenon called RNA interference [17].

3.2. miRNA in GBM

GBM is characterized by aberrations in miRNA expression. miRNAs either act as oncogenes or tumor suppressors and exert a major impact on oncogenic processes involving gliomagenesis, such as regulation of angiogenesis, metabolic pathways, and associated enzymes, or by regulating GSC (glioma stem cell) differentiation in GBM. miRNAs can regulate around 3% of all genes of glioma tumors and 30% of coding genes. Interestingly, one miRNA can control the expression of 100 mRNA associated with GBM [22]. miRNAs target metabolic reprogramming, a critical hallmark of GBM [23], which results in increased aerobic glycolysis in GBM compared to normal brains. Aerobic glycolysis is controlled by oncogenic signaling pathways and tumor suppressor genes; aberration in any of these genes may alter the expression of metabolic enzymes and the activity of metabolic transporters [23]. Expression of these glycolytic regulators and metabolic genes is targeted by miRNAs, such as miR-144, miR-155, miR-34a, and others [11].

3.3. Upregulated miRNA

miR-21

miRNA-21 was the first one reported as an oncogenic miRNA with an anti-apoptotic activity significantly contributing to the progression of GBM. It is highly upregulated in most tumors, particularly in GBM [24]. Thus, by downregulating miR-21 with subsequent caspase activation, the miR-21 anti-apoptotic effect can be reversed, which will ultimately aid in enhancing overall survival in GBM patients [6]. miR-21 is a key inhibitor of PTEN and p53, and an activator of EGFR, Cyclin D1, and AKT-2 [25].
miR-21 enhances EGFR expression by repressing PPAR alpha and VHL, with subsequent activation of beta-catenin and AP-1. Therefore, the silencing of miR-21 expression will decrease the oncogenic activity of EGFR, BCL2, and cyclin D, and it will lead to the upregulation of tumor suppressor proteins, such as Bax, p21, TGFBR2, or p53 [26]. Apart from having pro-proliferative activity, miR-21 also promotes tumor invasion and migration [27], as it induces tumor invasion by targeting regulators of matrix metalloproteinase, such as RECK (reversion inducing cysteine-rich protein with Kazal motifs) and TIMP3 (tissue inhibitor of metalloproteinase) [19][26]

3.4. miR-10b and miR-10a

These are oncogenic miRNAs commonly overexpressed in GBM [25]. miR-10a exhibits chemoresistance [27], while miR-10b significantly promotes GBM cell proliferation, invasion, migration, and EMT (epithelial–mesenchymal transition) [15], and it also imparts an oncogenic effect on GSC cells [27]. miR-10b expression levels correlate with clinical and WHO tumor grades [28]. miR-10b targets are cell cycle inhibitors [7], such as CDKN1A and CDKN2A, BIM, BCL2, TEAP2C, and PTEN, an antagonist of the PI3K pathway [11][15][27]. It promotes GBM cell invasion by enhancing RhoC (Ras homolog gene family member C) and uPAR (Urokinase-type plasminogen activator receptor) expression via modulation of HOXD10 expression [15].

3.5. miR-10b-miR-21

3.5.1. miR-10b and miR-222

miR-10b and miR-222 together contribute to oncogenic activity in GBM and are associated with poor survival [29]. Synergistically, they promote tumor progression and cell proliferation by targeting PTEN, which activates the p53 antitumor signaling pathway by suppressing MDM2, a key inhibitor of p53 [15][29]. They also regulate apoptosis in a p53/PTEN-independent manner directly by modulating the expression of BIM, an apoptotic initiation factor [29]. Thus, miR-10b and miR-222 can be potential therapeutic targets for the treatment of GBM [29].

3.5.2. miR-9

miR-9 overexpression in GBM with poor overall prognosis has been widely reported [11][25][30]. It promotes tumor cell proliferation, migration, and inflammation; it also indirectly regulates KRAS via targeting NF1, a KRAS inhibitor [11][30]. Overexpressed miR-9 has been observed to be positively correlated with GSC differentiation, thereby conferring chemoresistance to GBM [30]. miR-9 also induces TMZ resistance in CD133+ cells; therefore, miR-9 upregulation is an indicator of poor survival [30][31].

3.5.3. miR-221/222

miR221/222 overexpression is associated with the increase in tumor growth and other major hallmarks of cancer, such as proliferation, migration, invasion, and angiogenesis. It has an oncogenic influence on GBM, and it correlates with poor survival [7][14][15]. miR-221/222 cluster promotes all these malignant properties by increasing MMP2, MMP3, and VEGF along with its target Akt signaling pathway [14][15]. Other targets of miR-221/222 are PTEN, TIMP3, E2F3, and PUMA [14][32]. The miR-221/222 cluster displays anti-apoptotic activities by inhibiting PUMA, which is a proapoptotic gene, or by co-targeting the PTEN gene [26][32].

3.5.4. miR-26a

This miRNA is overexpressed in high-grade GBM, and its expression is associated with the degree of malignancy [33]. It acts as an oncogene by binding to the 3′ UTR of PTEN, leading to PTEN protein inhibition. MiR-26a overexpression in glioma cells circumvents the need for loss of heterozygosity of PTEN to promote tumor formation [7][11][25]. miR-26a expression has been found to be directly upregulated by MYC oncogene [33].

3.5.5. miR-17-92 Cluster

The expression of this miRNA cluster has been reported to be exceptionally higher in GBM than in normal healthy brain tissue. It employs its oncogenic effect on high-grade glioma and its elevated expression level associated with the aggressiveness of the tumor [34]. miR-17-92 higher expression correlates with GBM [35] and with GSC regulation [19]. It promotes GSC differentiation and exhibits an anti-apoptotic effect. It targets tumor suppressor genes and cell cycle inhibitors, such as PTEN and CDKN1A [34].

3.5.6. miR-148a

This miRNA promotes exosome-induced GBM, cell proliferation, and metastasis [36]. It has been acknowledged as one of the significant GBM-associated risky miRNAs by TCGA (The Cancer Genome Atlas) [36]. miR-148a level has been found to be excessively elevated in the serum of patients with GBM compared to normal healthy participants [36]. miR-148a exerts its oncogenic influence by directly targeting CADM1 (cell adhesion molecule 1), which is a tumor suppressor gene that inhibits cell motility and tumor proliferation [15][36].

3.5.7. Other Upregulated miRNA in GBM

miR-221, miR-125, miR-182, miR-196, miR-30, miR-143, miR-494-3p, miR-96a/96b, miR-182, miR-210, miR-503, and miR-378 have all been reported to be upregulated in GBM and contribute to gliomagenesis.
miR-221 targets cell cycle inhibitors [7] and promotes proliferation as well as potentially enhancing GBM cell migration and invasiveness [35].
miR-125 is an oncogenic miRNA and promotes the proliferation of GBM cells by targeting the anti-apoptotic gene BMF [25].
miR-182 and miR196 are both elevated in GBM [25]. miR-182 enhances the aggressiveness of glioma cells by targeting USP15, TNIP1, CYTLD, and OPTN, which disrupts the negative feedback loop of NF-kB. On the other hand, miR-196 increases glioma cell proliferation and poor survival in GBM patients [25].
miR-30 and miR-486 are oncogenic miRNAs and promote angiogenesis [25]. miR-30 is overexpressed in GSC, and it enhances its tumorigenicity by silencing SOCS3 (suppressor of cytokine signaling 3) along with inducing the JAK/STAT3 pathway [37]. It also induces resistance to glioma cells against TRAIL protein as well as inhibits apoptosis by binding to the 3′UTR of caspase 3 [37]. miR-30 has been observed to be negatively correlated with the survival of glioma patients [37].
miR-143 promotes glioma cell differentiation by targeting HKII [11]. miR-451 is an oncogenic miRNA; it upregulates in GBM and contributes to tumorigenesis by targeting the LKB39-AMPK pathway [11].
MiR-495-3p promotes proliferation, migration, and invasion by targeting the P13K/AKT tumor-suppressing signaling pathway [22]. miR-96a and 96b are oncogenic miRNAs that contribute to the poor overall survival of glioma patients [22]. miR-93 promotes angiogenesis and tumor growth [22]. miR-503 is upregulated in GBM and inhibits apoptosis by targeting PACD4 [15]. miR-378 targets VEGFR2 and promotes tumor growth and angiogenesis [15][17]. miR-201 is an oncogenic miRNA, significantly elevated in the serum of glioma patients. It is associated with high-grade glioma and poor overall survival [38].

3.6. Downregulated miRNAs

3.6.1. miR-31

It plays a pivotal role in tumor suppression by inhibiting invasion and migration via targeting the RDX gene (Radixin) [25].

3.6.2. miR-124

miRNA-124 has a low expression in high-grade glioma [39]. Its overexpression lowers SNAI2 levels, which results in suppression of GSCs invasiveness and of other stem-like traits that contribute to GBM malignancy [25]. It also induces cell cycle arrest directly by targeting CDK4, CDK6, and cyclin D. Hence, mir-124 inhibits glioma cell growth [39].

3.6.3. miR-34

miR-34a is downregulated in GBM, and, if expressed in tumor cells, it causes suppression of cell proliferation and invasion, controls GSC differentiation, stem-like traits, and cell cycle arrest by targeting Notch1, Notch2, CDK6, EGFR, and c-Met [22][40]. They also promote apoptosis by targeting Bcl-2 [41][42].

3.6.4. miR-302-367 Cluster

This miRNA targets GICs (glioma-initiating cells), which confer resistance to glioma cells against TMZ treatment, as well as inhibits the CXRC4 receptor, which, in turn, disrupts the SHH signaling pathway, thus resulting in preventing tumor progression [11].

3.6.5. miR-181

miR-181 is a family of four members (miR181a, miR-181b, miR-181c, and miR-181d), all of which are downregulated in GBM [24][43]. Among them, a significant reduction in expression levels of miR-181a and 181b has been observed in high-grade gliomas. These two members of miR-181 are routinely employed in distinguishing high-grade gliomas from low-grade gliomas [24]. miR-181a suppresses GSC-induced stemness and other tumorigenic effects via targeting CD133 and BMI1 stemness-related markers [24]. miR-181c expression decreases in GBM due to the absence of CTCF with concomitant epigenetic silencing by DNA methylation [8].

3.6.6. miR-219-5p and miR-219-1-3p

Downregulation of these miRNAs correlates with the increase in glioma cell proliferation. Their overexpression causes a reduction in tumor growth [22].

3.6.7. miR-1

miR-1 has a tumor-suppressing activity in GBM cells, as it has been observed that it inhibits the proliferation and migration of GBM cells when expressed ectopically [15][24][44]. Additionally, upon expression in glioma cells, they enhance the sensitivity of GBM cells toward TMZ induce apoptosis [44].

3.6.8. miR-370-3p

miR-370-3p is downregulated in both high- and low-grade glioma [14]. They suppress cell proliferation and migration by regulating the WNT signaling pathway via targeting the 3′UTR of β-catenin whose stabilization is pre-required for activation of WNT signaling [14].

3.6.9. miR-328

miR-328 lower expression suggests a poor overall survival rate in patients with GBM [24]. The downregulation of miR-328 in GBM tissues contributes to proliferation and tumor growth by enhancing cell division. miR-328 anti-proliferative activity can be used as a potential therapeutic target for GBM therapy [45].

3.6.10. miR-375

miR-375 is an anti-proliferative miRNA whose downregulation aids in the progression of glioma cell tumorigenesis by facilitating its cell proliferation, invasion, and migration [15][46].

3.6.11. miR-137

This is a tumor-suppressing miRNA that, on expression, provides protection from tumor progression by inhibiting angiogenesis via inhibition of EZH2 (enhancer of zest homology2), a key proliferation-inducing factor [15][17]. Thus, low expression of this miRNA often correlates with poor prognosis [15][17].

3.6.12. miR-128

This miRNA has a prolific role as a tumor-suppressing factor. Its low expression is associated with high-grade glioma. Therefore, miR-128 can be used to distinguish between low- and high-grade glioma [24]. miR-128 induces its tumor-suppressing effect, such as anti-proliferative and anti-metastasis effects, by inhibiting tumor-associated signaling pathways, such as WNT, ERK, EGFR, IGF1R, or BCL2 [15][19][22][47].

3.6.13. miR-7

miR-7 is downregulated in low-grade gliomas [11]. Consequently, the EGFR expression level increases, inducing upregulation of PKM2 via NF-κB activation, thus contributing to glioma tumorigenesis [11][22]. The other target of miR-7 is the AKT/PI3K signaling pathway [22].

4. miRNA and DNA Methylation: An Epigenetic Interplay in GBM

The complex epigenetic interplay between miRNA and DNA methylation has lately appeared to be quite intriguing to researchers. The monitoring of epigenetic changes during tumor progression can be quite useful to assess the efficacy of any epigenetic therapy, which might be used in combination with other established anti-tumor therapies in order to enhance their sensitivity and subdue the tumor-induced resistance against these therapies [48].
miRNA can either get modulated by epigenetic regulation or can, in turn, regulate those epigenetic modulators via feedback mechanisms. Thus, the epigenetic machinery and miRNA interaction can be considered potential targets for tumor therapies [48]. Most miRNAs are downregulated in GBM as a result of hypermethylation in the CpG island of their promoter region, a phenomenon of miRNA silencing via DNA methylation. There are plenty of miRNAs in GBM that are regulated epigenetically via DNA methylation.
miR-29a, miR-29b, and miR-29c constitute the miRNA-29 family of tumor-suppressing miRNAs that directly target DNA methyl transferases, such as DNMT3a and DNMT3b. As a result of this interaction, DNA methylation is repressed, hence suppressing tumor progression of glioma cells [49][50]
miR-211 promotes apoptosis by targeting MMP9 with concomitant activation of caspase-9/caspase-3 to inhibit tumor invasion. It has been reported to be downregulated in GBM due to epigenetic silencing via hypermethylation in its promoter region [49]
miR-181c is a tumor suppressor miRNA that is under-expressed in GBM due to DNA-methylation-induced repression. Its expression level inversely correlates with tumor invasion and proliferation [49]. miR-181c expression is regulated via CTCF and DNA methylation. CTCF is an 11-zinc finger highly conserved nuclear protein [14][22][27], which protects miR-181c repression from DNA methylation by binding to its CpG island region of their promoter.
miR-204 targets SOX4, a stem transcription factor, and prevents cell invasion. This miRNA is downregulated in GBM via DNA methylation [49]. miR-23 is another tumor-suppressing miRNA that causes cell cycle arrest but has been found to be inactivated epigenetically [49]. miR-137 inhibits GSC differentiation, but it is under-expressed in tumor cells and GSCs cells as a consequence of hypermethylation in their promoter region [49][51].

5. miRNA and Epigenetic Modifications in TMZ Response and Drug Resistance

5.1. Epigenetic Modulation and TMZ Response

MGMT is a DNA repair system considered a major contributor to TMZ resistance in GBM [52][53]. MGMT induces resistance to TMZ by removing a methyl group from O6-methylguanine, which results in the neutralization of TMZ-induced DNA damage, thus reducing the overall cytotoxic effect of TMZ [53]. Therefore, MGMT methylation status is often considered an important predictor of TMZ treatment response [6][53].

5.2. miRNA and TMZ Response

Besides their particular epigenetic actions, miRNAs have been reported to play important roles in TMZ resistance [52]. Several miRNAs have been observed to play regulatory roles in TMZ response: miR-195, miR-130a, miR-181a, miR-221, miR-21, miR-210, miR-222, and miR-10a. Apart from these, there are several other miRNAs that have been reported to be involved in MGMT regulation [53]. Upregulation of miR-370-3p, miR-603, miR-221/222, and miR-648 and downregulation of miR-181d, miR-370-3p, and miR-142-3p results in the inhibition of MGMT suppression, therefore, conferring chemoresistance to GBM cell against TMZ treatment [53].

6. Diagnostic and Prognostic Molecular Tools in 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]

7. GBM Therapy

7.1. miRNA Based Glioma Therapy

Several oncogenic and tumor-suppressing miRNAs that have a deep impact on tumor progression and their aggressiveness have been identified, and these miRNA signatures have led to the development of miRNA-based therapies, such as miRNA replacement therapy (Figure 1), oligonucleotide therapy (Figure 2), etc. Amongst several oncogenic miRNAs, miR-21 and miR-10b [56] have been used as potential targets of oligonucleotide therapy, and several studies have demonstrated their pre-clinical efficacy. Apart from this, several tumor-suppressive miRNAs have also been identified as potential therapeutic targets, such as miR-34a, miR-128, and miR-182 [56].
Figure 1. A flow chart of miRNAs replacement therapy, as a candidate experimental approach, but not yet used for therapy against GBM.
Figure 2. A flowchart of miRNA-based oligonucleotide therapy as a candidate experimental approach but not yet used for therapy against GBM.

7.2. Epigenetic Therapy

Epigenetics is one of the major mechanisms that contributes to and governs gliomagenesis. The epigenetic modulators that lead to epigenetic alterations can be potential therapeutic targets to try to reverse these epigenetic effects [59]. DNMT, enzymes, and genes, such as EZH2 and BMI1, are epigenetic modifiers [22]. The altered expression of enzymes has been identified as a pivotal epigenetic drug target for GBM treatment [59], and it is currently under preclinical and clinical trials [59].

7.3. Molecular Target Therapy

Molecular-based therapies use small molecule inhibitors or monoclonal antibodies to inhibit growth factor pathways, angiogenesis pathways, and intracellular signaling pathways, such as PI3K/AKT/mTOR, which are involved in GBM progression [3][60]. The mechanism behind this therapy employs drugs to block signaling pathways that promote cell growth [60]. Monoclonal antibodies, such as imatinib, inhibit PDGF, a promoter of tumor growth [3], and other pathways, such as RTKs, unfortunately, lack efficacy [3]. Similarly, gefitinib and erlotinib, which are anti-EGFR drugs, are under clinical trials, but they have not shown any promising outcomes. Contrary to these drugs, bevacizumab, a monoclonal antibody that targets VEGF, has shown promising therapeutic efficacies and has been observed to be effective in promoting progression-free survival during clinical trials [3]. The combinational therapy of bevacizumab with radiotherapy and TMZ is currently under clinical trial [3]. Thus, overall molecular-based therapeutic agents are still in trial stages I/II, and they lack the desirable efficacy due to high toxicity [3].

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