The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma
Abstract
1. Introduction
2. General Molecular Features
3. Glioblastoma Management
4. Clinical Relevance of the Molecular Profile
- Astrocytoma, IDH-mutant: Previously, IDH-mutant tumors were classified as diffuse astrocytoma, anaplastic astrocytoma, or GBM. The latest classification now consolidates these into a single type of IDH-mutant astrocytoma, graded as 2, 3, or 4.
- Grading criteria: The grading of IDH-mutant diffuse astrocytic tumors is no longer based solely on histology. It also considers the presence of the CDKN2A/B homozygous deletion mutation, which results in a CNS WHO grade of 4, even if microvascular proliferation or necrosis is absent.
- GBM, IDH-wildtype: This classification identifies specific molecular markers for this tumor, such as the presence of a TERT promoter mutation (associated with increased telomerase activity, crucial for tumor cell immortalization) or EGFR gene amplification, leading to overexpression of the receptor and the combined gain of chromosome 7 and loss of chromosome 10 (+7/−10). If any of these markers are found in an IDH-wildtype diffuse astrocytic glioma in adults, the diagnosis should be GBM, IDH-wildtype.
- Pediatric patients: The diagnostic criteria for IDH-wildtype diffuse astrocytomas differ in pediatric patients, who are diagnosed using different categories of pediatric-type gliomas [2].
- Proneural group: This group is characterized by proneural gene expression patterns and RTK I/LGm6 DNA methylation profiles. This subgroup often shows amplifications of genes such as cyclin-dependent kinase 4 (CDK4) and platelet-derived growth factor alpha (PDGFRA). It is more prevalent among younger adults.
- Classical group: This group exhibits classical gene expression patterns and classic-like RTK II DNA methylation profiles. It is marked by frequent EGFR amplifications and the loss of CDKN2A/B genes.
- Mesenchymal group: This group OS enriched for tumors with neurofibromatosis type 1 (NF1) loss and increased infiltration by macrophages [22]. This subgroup is associated with a mesenchymal or mesenchymal-like subtype.
5. microRNAs (miRNAs) and GBM
5.1. miRNAs Function and Biogenesis
5.2. miRNAs in Cancer
5.3. miRNAs in GBM
5.3.1. OncomiR-Upregulated miRNAs
OncomiR Involved in GBM Biogenesis
- miR-17-92 cluster
OncomiR Involved in GBM Prognosis
- miR-9
- miR-10a and miR-10b
- miR-148a
- miR-182
- miR-196a and miR-196b
OncomiR with Effect on Therapy Efficacy
- miR-26a
- miR-648
OncomiRs Involved in GBM Biogenesis That, in the Future, Will Have a Clinical Role Through Their Inhibition
- miR-21
5.3.2. Tumor-Suppressor miRNAs-Downregulated miRNAs
Tumor-Suppressor miRNAs Involved in GBM Biogenesis
- miR-1
Tumor-Suppressor miRNAs Involved in GBM Prognosis
- miR-128
- miR-137
- miR-181 family
Tumor-Suppressor miRNAs with Effect on Therapy Efficacy
- miR-370-3p
Tumor-Suppressor miRNAs Involved in GBM Biogenesis That, in the Future, Will Have a Clinical Role Through Their Inhibition
- miR-7
- miR-34
miRNA | Target | Expression in GBM | Function/Role in GBM if the miRNA is Overexpressed | Clinical Applications | References | |
---|---|---|---|---|---|---|
In Vitro | In Vivo | |||||
miR-9 | -RAS and MYC -PTCH1 | ↑ | Cancer cell proliferation↑ Tumor cell transformation↑ Inflammation↑ Angiogenesis↑ Apoptosis↓ | Overexpression can enhance the resistance to TMZ in GBM cells (p < 0.05). | Associated with short-term survivors. | [51,52,53,54,55] |
miR-10a, b | -CDKN1A, BIM, BCL2, TEAP2C, and PTEN -HOXD10 | ↑ | Cancer cell proliferation↑ Tumor cell migration↑ Invasion↑ EMT promotion↑ Apoptosis↓ GSC differentiation↑ | The expression is higher in GBM than in other gliomas. | [56,57,58,59,60,61,62] | |
miR-17-92 cluster | -Some cell-cycle inhibitors, such as PTEN and CDKN1A | ↑ | Cancer cell proliferation↑ Apoptosis↓ GSC differentiation↑ | This cluster is associated with high aggressiveness, higher invasion, and replication capability. | [48,49,50] | |
miR-21 | -PTEN, p53 -EGFR, Cyclin D1, and AKT2 -SPOCK1 -RECK and TIMP3 | ↑ | Cancer cell proliferation↑ Tumor cell migration↑ Invasion↑ | Hypothetically that silencing of this miRNA can be used, in the future, as a therapy in the treatment of GBM. | [35,48,56,59,86] | |
miR-26a | -PTEN, ATM | ↑ | Cancer cell proliferation↑ Invasion↑ | Overexpression, reducing DNA repair ability and enhancing radio sensitivity to radiotherapy. | [57,80,81,82] | |
miR-148a | -CADM1 -FIH1 | ↑ | Angiogenesis↑ Invasion↑ | Overexpressed in the plasma from the serum of GBM patients if compared to healthy cases. -Expressed in the high-risk group (i.e., patients characterized by low survival). | [56,64,65,66] | |
miR-182 | -BCL2L12 -HIF2A -MET -CYLD -LRRC4 | ↑ | Uncontrolled cell proliferation↑ Apoptosis↑ GSC differentiation↑ | Correlates with better response to TMZ based chemotherapy and with better survival (p = 0.01/p = 0.04). | [68,69,70] | |
miR-196a, b | -HOXB8, HOXC8, HOXD8, HOXA7, HOXB7 -ERG -HMGA2 -ANXA1 | ↑ | Cancer cell proliferation↑ Apoptosis↓ | Overexpression favors cells’ proliferation. | miR-196b expression correlated with OS (p = 0.01). | [75,76,77,78,79] |
miR-648 | -MOBP | ↑ | Cancer cell proliferation↑ Invasion↑ | The expression by transfection enhanced responsivity of TMZ in MGMT-expressing T98G glioma cells. | Correlation between OS and miR-648 expression. | [79,83,84,85] |
miRNA | Target | Expression in GBM | Function/Role in GBM if the miRNA Expression is Inhibited | Clinical Applications | References | |
---|---|---|---|---|---|---|
In Vitro | ||||||
miR-1 | -Connexin-43 -G6PD | ↓ | Cancer cell proliferation↑ Tumor cell migration↑ Apoptosis↓ | Inhibition can enhance the cells proliferation and the sensitivity of GBM cells towards TMZ. | [56,87,88,89] | |
miR-7 | -EGFR, AKT/PI3K pathway -PKM2 | ↓ | Cancer cell proliferation↑ GSC differentiation↑ | Transfection in U373-MG GBM cell line resulted in significant suppression of EGFR mRNA and protein, leading to the inhibition of cells’ duplication. | [35,97,98] | |
miR-34 | -Bcl2, NOTCH, NUMB -CDK6 -EGFR -c-Met | ↓ | Cancer cell proliferation↑ Apoptosis↓ Invasion↑ | -In GSC cultures, the infection by ZIKV induced miR-34 expression, inhibiting the anti-apoptotic protein Bcl-2 and Numb, involved in GSC invasion. -In mouse models, ZIKV reduced brain tumor size and metastasis. | [99,100,101,102,103,104,105,106] | |
miR-128 | -WNT -ERK -EGFR -IGF1R -Bcl2 -PDGFRA -Caspase | ↓ | Cancer cell proliferation↑ Apoptosis↓ | The low expression can be associated with high-grade glioma cell lines and, consequently, a worse prognosis. | [56,90,91] | |
miR-137 | -EZH2 | ↓ | Cancer cell proliferation↑ Apoptosis↓ Angiogenesis↑ | Expression level of miR-137 was downregulated in GBM cells. | The low level of this miRNA was related to poor prognosis in GBM patients. | [56,92,93] |
miR-181 family | -CD133 and BMI1 CCN1 | ↓ | Cancer cell proliferation↑ GSC differentiation↑ Apoptosis↓ Invasion↑ | -Low level of expression was related to poor prognosis in GBM patients. -Low level of expression of miR-181c or low expression of miR-181d, in combination with expression of miR-648, predicts the worst prognosis. | [78,84,87,94] | |
miR-370-3p | -WNT -FOX01, FOXM1 and TGFβ. | ↓ | Cancer cell proliferation↑ Invasion↑ | When miR-370-3p is upregulated, GBM growth is inhibited. | [95,96] |
5.4. Exosomal miRNAs and Cancer
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Epistolio, S.; Spina, P.; Zaed, I.; Cardia, A.; Marchi, F.; Frattini, M. The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma. Int. J. Mol. Sci. 2025, 26, 2723. https://doi.org/10.3390/ijms26062723
Epistolio S, Spina P, Zaed I, Cardia A, Marchi F, Frattini M. The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma. International Journal of Molecular Sciences. 2025; 26(6):2723. https://doi.org/10.3390/ijms26062723
Chicago/Turabian StyleEpistolio, Samantha, Paolo Spina, Ismail Zaed, Andrea Cardia, Francesco Marchi, and Milo Frattini. 2025. "The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma" International Journal of Molecular Sciences 26, no. 6: 2723. https://doi.org/10.3390/ijms26062723
APA StyleEpistolio, S., Spina, P., Zaed, I., Cardia, A., Marchi, F., & Frattini, M. (2025). The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma. International Journal of Molecular Sciences, 26(6), 2723. https://doi.org/10.3390/ijms26062723