Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review

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MicroRNAs (miRNAs), influential in cancer research, show potential as glioma biomarkers. This systematic review aimed to examine the efficacy of miRNAs in the diagnosis and prognosis of high-grade glioma. Methods A comprehensive search was conducted of PubMed, EMBASE, Cochrane Library, and Web of Science for studies published from 2013 to 2023. The eligibility criteria included high-grade glioma, histopathological confirmation, miRNA samples from cerebrospinal fluid or plasma, and relevant outcome data. Studies were excluded if they were experimental or reviews and not in English. Results Of the 1120 initial results, 8 studies involving 660 subjects met the inclusion criteria. Several studies have assessed miRNA expression and its association with diagnosis and prognosis of high-grade gliomas. Overexpression of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and under-expression of miR-15b and miR-124-3p showed significant potential in differentiating high-grade glioma patients from controls. Additionally, miRNAs are associated with distinct tumorigenic pathways. Conclusion Elevated or depressed expression levels of specific circulating miRNAs hold significant promise as noninvasive biomarkers for the diagnosis and prognosis of high-grade glioma. These miRNAs offer valuable insights into disease progression and patient outcome. Further validation through extensive clinical trials and in-depth mechanistic studies is essential to realize their full clinical utility. 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F1000Research 2025, 13 :796 ( https://doi.org/10.12688/f1000research.151350.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] Renindra Ananda Aman https://orcid.org/0000-0002-5135-6256 1 , Mohammad Galih Pratama 1 , Ricky Rusydi Satriawan https://orcid.org/0009-0006-7894-5217 1 , Irfani Ryan Ardiansyah 1 , I Ketut Agus Suanjaya 1 Renindra Ananda Aman https://orcid.org/0000-0002-5135-6256 1 , Mohammad Galih Pratama 1 , [...] Ricky Rusydi Satriawan https://orcid.org/0009-0006-7894-5217 1 , Irfani Ryan Ardiansyah 1 , I Ketut Agus Suanjaya 1 PUBLISHED 15 Jan 2025 Author details Author details 1 Department of Neurosurgery, Faculty of Medicine, University of Indonesia, Jakarta, DKI Jakarta, Indonesia Renindra Ananda Aman Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Mohammad Galih Pratama Roles: Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Ricky Rusydi Satriawan Roles: Data Curation, Investigation, Validation, Writing – Review & Editing Irfani Ryan Ardiansyah Roles: Methodology, Resources, Software, Validation, Visualization, Writing – Review & Editing I Ketut Agus Suanjaya Roles: Methodology, Project Administration, Resources, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Cell & Molecular Biology gateway. Abstract Background Gliomas, particularly glioblastomas, have grim prognoses, necessitating early diagnostic and prognostic indicators. MicroRNAs (miRNAs), influential in cancer research, show potential as glioma biomarkers. This systematic review aimed to examine the efficacy of miRNAs in the diagnosis and prognosis of high-grade glioma. Methods A comprehensive search was conducted of PubMed, EMBASE, Cochrane Library, and Web of Science for studies published from 2013 to 2023. The eligibility criteria included high-grade glioma, histopathological confirmation, miRNA samples from cerebrospinal fluid or plasma, and relevant outcome data. Studies were excluded if they were experimental or reviews and not in English. Results Of the 1120 initial results, 8 studies involving 660 subjects met the inclusion criteria. Several studies have assessed miRNA expression and its association with diagnosis and prognosis of high-grade gliomas. Overexpression of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and under-expression of miR-15b and miR-124-3p showed significant potential in differentiating high-grade glioma patients from controls. Additionally, miRNAs are associated with distinct tumorigenic pathways. Conclusion Elevated or depressed expression levels of specific circulating miRNAs hold significant promise as noninvasive biomarkers for the diagnosis and prognosis of high-grade glioma. These miRNAs offer valuable insights into disease progression and patient outcome. Further validation through extensive clinical trials and in-depth mechanistic studies is essential to realize their full clinical utility. READ ALL READ LESS Keywords miRNA, Glioma, Biomarker, Prognostic, Oncogene Corresponding Author(s) Renindra Ananda Aman ( [email protected] ) Close Corresponding author: Renindra Ananda Aman Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Aman RA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Aman RA, Pratama MG, Satriawan RR et al. Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.12688/f1000research.151350.2 ) First published: 15 Jul 2024, 13 :796 ( https://doi.org/10.12688/f1000research.151350.1 ) Latest published: 15 Jan 2025, 13 :796 ( https://doi.org/10.12688/f1000research.151350.2 ) Revised Amendments from Version 1 ⁠⁠We have made sure that the terminology "miRNA" is used in our study, not "mRNA." ⁠⁠In the Methods section, we added a sentence explaining that the flowchart will be displayed in the Results section. ⁠⁠From the Results to the Discussion sections, we have adjusted and verified all citations used in our study. ⁠⁠In the Discussion section, one paragraph has been added providing a brief overview and highlighting the significance of miRNA. ⁠⁠We have made sure that the terminology "miRNA" is used in our study, not "mRNA." ⁠⁠In the Methods section, we added a sentence explaining that the flowchart will be displayed in the Results section. ⁠⁠From the Results to the Discussion sections, we have adjusted and verified all citations used in our study. ⁠⁠In the Discussion section, one paragraph has been added providing a brief overview and highlighting the significance of miRNA. See the authors' detailed response to the review by Dessika Rahmawati READ REVIEWER RESPONSES 1. Introduction Gliomas, a class of tumors originating in the central nervous system, pose a formidable medical challenge given their grim prognosis and complex nature. Glioblastoma is the most prevalent form among adults, with an incidence rate of 6.34 cases per 100,000 individuals. 1 This aggressive tumor is characterized by rapid growth, often progressing for weeks or months. Despite the implementation of a multimodal therapeutic approach involving surgery, radiotherapy, and chemotherapy, the average survival for glioblastoma patients is only 15 months. 2 Against this backdrop of clinical urgency, the search for early diagnostic and prognostic indicators for gliomas is of paramount importance. Gliomas are the most common and aggressive type of primary brain tumor in adults. It should be noted that, for gliomas, malignancy (e.g., anaplastic astrocytoma and glioblastoma) can arise de novo or progress from the lower grade. Despite all the achievements of modern medicine, the prognosis for patients with high-grade gliomas remains unsatisfactory. 3 MicroRNAs (miRNAs) have emerged as a captivating subject of study within the realm of cancer research, owing to their intricate involvement in the disease’s intricate molecular landscape. Comprising a class of small, non-coding RNAs composed of 19 to 22 nucleotides, miRNAs have a powerful influence on gene expression and cellular processes. 4 Of note is their role in tumorigenesis, where alterations in miRNA target binding sites and disruptions in the miRNA processing machinery within tumor cells have been identified as significant contributors to cancer development and progression. 5 This burgeoning field of research has delved into the depth of miRNA expression patterns in gliomas, yielding captivating insights into their diagnostic and prognostic potential. A growing body of evidence underscores the intricate correlations between specific miRNAs and the clinical aspects of gliomas, which have shown promise not only as potential biomarkers for early detection but also as indicators of disease progression and therapeutic response. 5 – 8 By elucidating the complex web of miRNA-glioma associations, researchers aim to unlock a treasure trove of information that could ultimately revolutionize the diagnosis, treatment, and management of this relentless disease. This review aims to examine the effectiveness of miRNAs in the diagnosis and prognosis of high-grade gliomas. 2. Methods 2.1 Search strategy We carefully searched the literature using online free accessed software Rayyan ( https://new.rayyan.ai/ ) with literature databases such as PubMed ( https://pubmed.ncbi.nlm.nih.gov/ ), EMBASE ( https://www.embase.com/landing?status=grey ), Cochrane Library ( https://www.cochranelibrary.com/ ), and Web of Science ( https://www.webofscience.com/wos ) to identify relevant studies published between 2013 and 2023 using the following strategy: (((((microrna) OR (mirna)) OR (mirnas) AND (y_5[Filter])) AND (((((high grade glioma) OR (glioblastoma)) OR (anaplastic astrocytoma)) OR (anaplastic oligodendroglioma)) OR (anaplastic oligoastrocytoma) AND (y_5[Filter]))) AND (((diagnostic) OR (diagnosis)) OR (early diagnosis) AND (y_5[Filter]))) AND ((prognostic) OR (survival) AND (y_5[Filter])) Filters: in the last 5 years. 2.2 Eligibility criteria The selection process for studies to be included in this study adhered to stringent eligibility criteria. Studies were deemed eligible if they satisfied the following criteria: high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, as confirmed by histopathological examination. miRNA samples were collected from cerebrospinal fluid or plasma. For prognostic studies, the inclusion criterion required survival curves depicting overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), or recurrence-free survival (RFS). These survival curves were expected to be accompanied by hazard ratios (HR) and the corresponding 95% confidence intervals (CIs). Conversely, diagnostic studies are required to present data encompassing true positive, true negative, false positive, and false negative outcomes. Studies were excluded if they were categorized as experimental studies, review articles, or letters. Studies that were not conducted on human subjects and those that were not published in English were excluded. These rigorous inclusion and exclusion criteria were used to ensure the selection of studies that met the stringent standards of scientific rigor and relevance for research. Flow chart showing study selection process will be displayed at result section. 2.3 Data extraction and quality assessment Two independent authors collected the study characteristics and original data, including the first author’s name, publication year, study design, study population, population size, age and sex of participants, follow-up duration, sample type, method of measuring miRNA expression, and HRs and their 95% CIs. Studies were included according to the following checklist based on the criteria provided by the MOOSE group: clearly defined study design; clearly described study population (country); sufficiently large sample (N>30); clearly described outcome (OS, CSS, DFS, or RFS); clearly defined miR measurement, including quantitative real-time polymerase chain reaction (qRT-PCR) or in situ hybridization (ISH); clear definition of cut-off values; miR measurement in tumor tissue, plasma, or serum; and sufficiently long follow-up. Studies that did not meet these criteria were excluded. Quality assessment was performed using the Cohcrane’s risk of bias in non-randomized studies of interventions (ROBINS-I) tool. Any discrepancies regarding the risk of bias judgments were resolved by discussion until agreement was reached. Certainty of evidence refers to the confidence that the observed effects of mRNA expression levels and their implications in glioma accurately reflect their true biological and clinical impact. Using the GRADE framework, factors such as study design, risk of bias, consistency of results, directness of evidence, precision of estimates, and publication bias were assessed meticulously. A high certainty of evidence suggests that further research is unlikely to significantly alter the current understanding, whereas low certainty indicates that new studies could substantially impact the conclusions. This rigorous evaluation ensured that the systematic review provided a reliable foundation for advancing research and informing clinical practices related to mRNA and glioma. 3. Results 3.1 Overview of study selection A Literature search yielded 1120 results, of which 8 studies met the criteria, with a total of 660 subjects. The complete search process is illustrated in Figure 1 . Figure 1. PRISMA study selection process diagram. 3.2 Characteristics of included studies The quality assessment of each study is shown in Figure 2 . The characteristics of the included studies are presented in Table 1 . A total of 660 participants were included in this study. The sample size of each study ranged from 39 to 152 patients. The majority of the studies (n = 5) were conducted in China, and the remainder were conducted in, Italy (n = 2), and Russia (n = 1). One study conducted observations and follow-ups after 48, 60, > 60, and > 100 weeks. Most studies have used qRT-PCR to detect and measure the expression levels of miRNAs. In addition to diagnosis, the study assessed prognosis by calculating HRs and 95% Cis. A summary of each miRNA, its potential targets, and pathways is presented in Table 2 . Figure 2. Results of study quality assessment using the ROBINS-I tool (a) domain specific quality assessment graph. Table 1. Characteristics of Studies in Included in Our Review. miRNA Study Country n Sample Sample source Control (n) Measurement WHO Classification Follow-up Hazard ratio 95% CI p-value miR-221 Zhang et al, 2016 9 China 50 Peripheral venous blood Venous blood from non-glioma patient (50) qRT-PCR 2007 48 2.4 1.42-4.05 0.001 miR-222 Zhang et al, 2016 9 China 50 Peripheral venous blood Venous blood from non-glioma patient (50) qRT-PCR 2007 48 2.81 1.70-4.65 0.001 miR-210 Lai et al, 2014 10 China 125 Glioma tissue Brain tissue from non-glioma patient 10 qRT-PCR 2007 >100 2.3 1.47-3.61 0.003 miR-15b Sun et al, 2015 11 China 92 Glioma tissue Brain tissue from non-glioma patient 12 qRT-PCR 2007 >60 2.21 1.36-3.6 0.001 miR-21 Wu et al, 2013 12 China 152 Glioma tissue Adjacent non-glioma tissue (152) qRT-PCR 2007 60 3.17 2.39-4.18 0.001 miR-125b Li et al, 2016 13 China 45 Glioma tissue Adjacent non-glioma tissue (45) qRT-PCR 2007 >100 2.43 1.13-2.54 0.023 miR-21 Olioso et al, 2021 14 Italy 57 Peripheral venous blood Peripheral venous blood of the patient at follow up (57) qRT-PCR 2007 >60 0.4 0.13-1.43 0.017 miR-222 Olioso et al, 2021 14 Italy 57 Peripheral venous blood Peripheral venous blood of the patient at follow up (57) qRT-PCR 2007 >60 0.4 0.13-1.38 0.003 miR-124-3p Olioso et al, 2021 14 Italy 57 Peripheral venous blood Peripheral venous blood of the patient at follow up (57) qRT-PCR 2007 >60 0.4 0.13-1.38 0.022 miR-21 Barbano et al, 2014 15 Italy 32 Glioma tissue Brain tissue from non-glioma patient 4 qRT-PCR 2007 >60 1.19 1.01-1.41 0.04 miR-223 Stupak et al, 2023 16 Russia 107 Glioma tissue Adjacent non-glioma tissue (107) qRT-PCR 2007 48 1.1 1.00-1.22 0.046 Table 2. Summary of miRNA, potential targets, and pathways. miRNA Expression Pathways Target miR-221 9 Increased Cell cycle, proliferation, migration, apoptosis p27Kip1, PTPμ, PUMA miR-222 9 , 14 Increased Cell cycle, proliferation, migration, apoptosis p27Kip1, PTPμ, PUMA miR-210 10 Increased Proliferation, angiogenesis FGFRL1, GPD1L miR-15b 11 Decreased Cell cycle, apoptosis, invasion, angiogenesis cyclin D1, NRP, MMP-3 miR-21 12 , 14 Increased Angiogenesis, apoptosis, resistance to radio and chemotherapy HIF-1a and VEGF, PDCD4, hMSH2 miR-125b 13 Increased Growth and differentiation of CSCs, apoptosis E2F2, p53, p38MAPK miR 124-3p 14 Decreased Cell cycle, angiogenesis CDK6 kinase miR-223 16 Increased Proliferation IL-1β, MCP-1), IL-8 and IL-18 Eight studies were assessed 9 – 16 and 4 studies had a low risk of bias in the overall domain. 9 – 11 , 16 Meanwhile, three studies were concerned with qualitative measure. 5 , 11 , 12 , 15 One study has critical judgement. 13 Three studies had bias due to the selection of participants because of the variances of the participants’ characteristics. 9 , 14 , 15 One study had bias owing to confounding variables. 14 One studies had some bias due to missing data in some specific miRNA expression. 9 Four studies have some attrition bias because of many outcomes reported in the studies. 11 – 14 One study had a critical bias due to the heterogeneity of the participants. 13 Lastly, one study had a serious risk of bias due to the measurement mechanism of the outcomes. 11 A summary of the GRADE assessment for each study is presented in Table 3 . Of the eight studies included in this systematic review, six were rated high and two were rated moderate. The true effect from each study was close to the estimate of the effect. Table 3. Assessment of certainty of each evidence. Certainty assessment Effect Quality of evidence (GRADE) No Journals Study Desain Risk of bias Inconsistency Indirectness Imprecision Other considerations Relative (95% CI) 1 Evgeny V. Stupak, 2023 Observational Low Not serious Not serious Not serious None HR 1.228 (1.073-1.407) ⊕⊕⊕⊕ High 2 Raffaela Barbano, 2014 Observational Low Not serious Not serious Not serious None HR 1.19 (1.01-1.41) ⊕⊕⊕⊕ High 3 Nian-sheng Lai, 2013 Observational Low Not serious Not serious Not serious None PFS p<0.001 (1.58-3.69) ⊕⊕⊕⊕ High 4 Xinxing Li, 2014 Observational Low Not serious Not serious Not serious None HR 2.43 (1.13-2.54) ⊕⊕⊕⊕ High 5 Debora Olioso, 2021 Observational Low Not serious Not serious Serious None PFS 8.5 (1-41) ⊕⊕⊕⊝ Moderate 6 Guan Sun, 2015 Observational Low Serious Not serious Not serious None Not Measured ⊕⊕⊕⊝ Moderate 7 Lin Wu, 2013 Observational Low Not serious Not serious Not serious None HR 3.17 (2.39-4.179) ⊕⊕⊕⊕ High 8 Rui Zhang, 2014 Observational Low Not serious Not serious Not serious None HR 2.81 (1.70-4.65) ⊕⊕⊕⊕ High GRADE indicates Grading of Recomendations, Asessment, Development, and Evaluation; HR, Hazard Ratio; PFS, Progression-Free Survival 1 High We are very confident that the true effect lies close to that of the estimate of the effect. 2 Moderate We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. 3 Low Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. 4 Very Low We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. 4. Discussion Gliomas, the most prevalent and aggressive form of primary brain tumors in adults, continue to present a daunting challenge despite medical advancements. Currently, the treatment approaches for high-grade gliomas rely on surgical procedures, radiation therapy, and chemotherapy. Regrettably, these methods, whether used individually or in combination, struggle to effectively control the disease, resulting in an average life expectancy of just over 12-15 months post-diagnosis. 2 Consequently, the importance of timely diagnosis and prognostication remains unclear. The concept of molecular biomarkers has made substantial progress in the past decade, offering insights into glioma pathogenesis, aiding early tumor detection, risk assessment for recurrence, treatment strategy adjustments, and ultimately, improved prognosis. 4 Among which, circulating miRNAs have emerged as a prominent focus of research. Although not yet integrated into clinical practice, advancements in this domain suggest that circulating miRNAs may play a pivotal role in high-grade glioma diagnosis and prognosis, potentially replacing the specific elements of contemporary diagnostic procedures. Our findings revealed that miR-210, miR15b, miR-21, miR-125b, miR 223 could be extracted from glioma tissues. miR-21, miR-221, miR-222, and miR-124-3p can be extracted from blood, indicating their potential as early diagnostic and prognostic tools for gliomas prior to surgery. Different tissues were used as controls in glioma studies. Wu et al, 12 Li et al, 13 and Stupak et al, 16 used adjacent non tumor tissue from the same glioma patient. Lai et al, and Sun et al, used samples of normal brain tissue collected from the internal decompression surgery on patients with cerebral injury and cerebral hemorrhage. 10 , 11 Barbano et al, used RNAs from four healthy individuals consists different brain regions (parietal cortex, frontal cortex, occipital cortex, and striatum). 15 In using blood as a source of miRNA, there were also differences between different study. Zhang et al, used venous blood from other non-tumor patient. 9 While Olioso et al, used blood from the same patient which were taken repeatedly along the duration of radio- and chemotherapy. 14 As an overview, miRNA could serve as diagnostic, prognostic, and monitoring biomarker for high grade glioma. Zhang et al has demonstrated that miR-221 and miR-222 has good diagnostic value (AUC 0.83). 9 On the other hand, Olioso et al further demonstrated that miR-21, miR-222, and miR-123-3p can be used to predict response to therapy. High level of miR-21, -222 and -124-3p during post-operative follow-up was associated with tumor progression. miR-21 was the earliest biomarker to predict response of therapy at 17 week post op, with progression free survival ratio (high/low) 0.7 (CI 0.34 – 1.42). 14 As prognostic biomarker, Wu et al showed correlation between expression level of miR-21 and grading of glioma (p < 0.005). Kaplan-Meier survival curves suggested that survival time of glioma patients with high miR-21 was significantly shorter compared to those with low miR-21 expression (p < 0.001). Further analysis of each miRNA will be described below. 12 4.1 Role of miRNAs in glioma miR-221/miR-222 The expression levels of miR-221 and miR-222 were higher in patients with gliomas than in the controls (P = 0.001). These miRNAs could potentially serve as biomarkers to distinguish glioma patients from controls, with an AUC of 0.83 (95% CI 0.74–0.93) for miR-221 and 0.88 (95% CI 0.79–0.98) for miR-222. The correlation between miR-221/222 expression and glioma prognosis may be partly explained by their role in promoting glioma cell proliferation through the downregulation of p27Kip1 expression. Additionally, miR-221/miR-222 are implicated in glioma cell migration by suppressing PTPμ expression and targeting apoptosis through direct binding to the 3’UTR mRNA region of the PUMA gene. 9 , 14 miR-210 The expression levels of miR-210 were significantly elevated in both high-grade (grade III–IV; 6.58 ± 1.42) and low-grade (grade I–II; 4.70 ± 0.93) gliomas compared to normal brain tissues (both p < 0.001). High-grade glioma tissues (III–IV) exhibited a significantly higher expression of miR-210 compared to low-grade tissues (I–II) (p < 0.001). miR-210 regulates glioma cell proliferation by targeting FGFRL 1, and under hypoxic conditions, it establishes a positive feedback loop that enhances HIF-1a stability by suppressing GPD1L, leading to the induction of genes associated with energy metabolism, angiogenesis, cell proliferation, and survival. 10 miR-15b miR-15b expression in human glioma tissues was significantly lower than that in the adjacent normal brain tissues (p < 0.01). Moreover, the expression of miR-15b in both grade III and IV glioma tissues was significantly lower than that in grade I–II gliomas (p < 0.01). Overexpression of miR-15b inhibits proliferation by arresting cell cycle progression and inducing apoptosis by directly targeting cyclin D in gliomas. It was reported that miR-15b reduced glioma cell invasion and angiogenesis through NRP and MMP-3. 11 miR-21 miR-21 expression was significantly (P < 0.001) higher in glioma tissues (20.99 ± 13.04) than in the corresponding non-neoplastic brain tissues (0.73±0.05). miR-21 expression in high-grade (III-IV) gliomas was higher than that observed in low-grade (I-II) gliomas (P < 0.001).9 In the T98G glioma cell line, the level of expression of the PDCD4 gene showed an inverse relationship with the expression of miR-21, and its reduction led to the inhibition of apoptosis. Overexpression of miR-21 in DU145 cells leads to elevated levels of HIF-1a and VEGF, promoting tumor angiogenesis.15 Elevated serum miR-21 levels have been identified as an indicator of a poorer response to trastuzumab. Resistant response to radiotherapy and temozolamide has been demonstrated to be mediated by miR-21. 12 miR-125b miR-125b revealed higher expression in glioma patients than controls (P < 0.001) and could potentially serve as a biomarker with an AUC of 0.83 (95% CI 0.74–0.93). miR-125b influences glioma stem cell proliferation by directly targeting E2F2. Additionally, it interacts with the 3′UTR of the apoptosis protein Bcl-2 modifying factor, inhibiting cell apoptosis through p53 and p38MAPK-independent pathways. 13 miR-223 The expression of miR-223 was significantly higher in grade IV glioma tissues than in adjacent normal tissues (p = 0.014), but no significant differences were observed between the different glioma grades. There is conflicting evidence regarding whether miR-223 acts as a tumor suppressor or oncogene in glioblastoma. Ding et al discovered that the overexpression of miR-223-3p hinder cell proliferation and migration in glioblastomas by controlling inflammation-associated cytokines. 16 miR-124-3p miR-124-3p demonstrated lower expression in grade IV glioma patients compared to controls (P = 0.028), with no significant differences between different grades. Functioning as a tumor suppressor, miR-124 regulates the cell cycle at G0/G1 and inhibits CDK6 kinase, thereby suppressing angiogenesis and promoting neuronal differentiation. 14 4.2 Prognostic significance of MiRNA in high-grade glioma Several miRNAs have shown promise as potential prognostic markers for high-grade gliomas, providing valuable insights into disease progression and patient outcome. High-grade gliomas, known for their aggressiveness, require accurate prognostic tools to guide their treatment. In this context, the Hazard Ratio (HR) is a critical statistical measure used to assess the prognostic significance of miRNAs. 13 HR represents the ratio of the risk of an event, such as disease progression or mortality, between two groups: one with high miRNA expression and the other with low expression. An HR greater than 1 indicates a higher risk of the event in the high-expression group, suggesting an unfavorable prognosis, while an HR less than 1 signifies a lower risk, implying a potentially better outcome. 10 By analyzing the HR associated with specific miRNAs, researchers can identify those that have a substantial impact on high-grade glioma prognosis. These miRNAs not only offer prognostic value but also hold the potential to guide personalized treatment strategies, ultimately improving patient care and outcomes in this challenging condition. Eight miRNAs and their abilities to predict glioma prognosis were investigated in this study. Patients with high levels of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and low levels of miR-15b and mir-124-3p expression had a significantly higher HR than those with low expression levels. HR represents the ratio of the risk of disease progression or mortality between groups with high and low miRNA expression. The use of miRNAs as noninvasive biomarkers for the diagnosis and prognosis of high-grade gliomas offers several advantages. First, miRNAs can be easily detected in various bodily fluids, such as blood or cerebrospinal fluid, eliminating the need for invasive procedures such as brain biopsies. 9 This noninvasive approach not only reduces patient discomfort but also lowers the associated risks and costs. Secondly, miRNAs exhibit remarkable specificity, allowing the identification of glioma-specific miRNA signatures. This precision aids in accurate diagnosis and can potentially differentiate high-grade gliomas from other brain conditions, thereby enhancing the diagnostic certainty. Furthermore, miRNAs play critical roles in tumor development and progression, making them valuable indicators of disease aggressiveness and patient prognosis. 14 Their ability to reflect dynamic changes in tumor biology over time enables clinicians to tailor treatment strategies for individual patients. In summary, miRNAs serve as noninvasive, specific, and dynamic biomarkers that hold great promise for transforming the diagnosis and prognostication of high-grade glioma and improving patient care and outcomes. Although assessing miRNA expression levels holds promise for predicting glioma prognosis, several challenges must be addressed before using miRNAs in clinical settings. First, cell-free miRNAs can be released from normal human tissues, potentially interfering with results. It is crucial to pinpoint the origin of tumor-specific miRNAs and develop a method capable of effectively distinguishing cancer populations from healthy individuals. Second, there is no standardized procedure for measuring miRNA levels, leading to conflicting findings. Furthermore, a single miRNA can be associated with various tumor types. 2 For instance, miR-21’s prognostic significance has been established in breast cancer, pancreatic ductal adenocarcinoma, and gastric cancer patients. 4 Therefore, identifying a set of miRNAs specific to glioma holds great promise and could significantly enhance prognostic accuracy. 4.3 Strengths and limitations The strength of this review article lies in its comprehensive assessment of both the diagnostic and prognostic approaches for miRNAs in the context of various medical conditions. By covering a wide spectrum of applications, this study offers a holistic view of the potential use of miRNAs in medicine. This is validated by country variability, study centers, and various patient characteristics, which suggest broad generalizability. Additionally, the studies included in this review were meticulously evaluated using standardized parameters to ensure the reliability and consistency of the findings. This finding was coupled with the specific types, targets, and mechanisms of each potential miRNA included in the highlighted findings. This rigorous approach enhanced the credibility of the conclusions and recommendations of this study. This study had some limitations. One notable limitation was the scarcity of studies that met the eligibility criteria for inclusion. The paucity of relevant research may limit the breadth of the review and ability to draw definitive conclusions regarding certain aspects of the diagnostic and prognostic utility of miRNAs. This scarcity may also introduce potential bias in the interpretation of available data. A quantitative review with a larger sample size is required to verify the statistical significance of the expression of each miRNA. Despite these limitations, this review provides valuable insights into the current state of knowledge on the diagnostic and prognostic potential of miRNAs. Ethics and consent Ethical approval and consent were not required. Data availability Underlying data No data is associated with this article. Reporting guidelines Figshare: PRISMA checklist for ‘Diagnostic and prognostic values of miRNAs in high-grade gliomas: A systematic review’. https://doi.org/10.6084/m9.figshare.26140279 Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements None. References 1. Wang J, Chen J, Sen S: MicroRNA as biomarkers and Diagnostics. J. Cell. Physiol. 2015 Sept 28; 231 (1): 25–30. PubMed Abstract | Publisher Full Text | Free Full Text 2. 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PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 15 Jul 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Neurosurgery, Faculty of Medicine, University of Indonesia, Jakarta, DKI Jakarta, Indonesia Renindra Ananda Aman Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Mohammad Galih Pratama Roles: Data Curation, Formal Analysis, Investigation, Writing – Review & Editing Ricky Rusydi Satriawan Roles: Data Curation, Investigation, Validation, Writing – Review & Editing Irfani Ryan Ardiansyah Roles: Methodology, Resources, Software, Validation, Visualization, Writing – Review & Editing I Ketut Agus Suanjaya Roles: Methodology, Project Administration, Resources, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 15 Jan 2025, 13:796 https://doi.org/10.12688/f1000research.151350.2 version 1 Published: 15 Jul 2024, 13:796 https://doi.org/10.12688/f1000research.151350.1 Copyright © 2025 Aman RA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Aman RA, Pratama MG, Satriawan RR et al. Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.12688/f1000research.151350.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 15 Jan 2025 Revised Views 0 Cite How to cite this report: Huang APH. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r364631 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-364631 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Feb 2025 Abel Po-Hao Huang , National Taiwan University Hospital, Taipei, Taiwan Approved VIEWS 0 https://doi.org/10.5256/f1000research.176321.r364631 This article indicates that specific miRNAs, such as miR-221, miR-222, and miR-21, are associated with poor prognosis and could serve as valuable indicators of disease progression. The article emphasizes the need for further validation through extensive clinical ... Continue reading READ ALL This article indicates that specific miRNAs, such as miR-221, miR-222, and miR-21, are associated with poor prognosis and could serve as valuable indicators of disease progression. The article emphasizes the need for further validation through extensive clinical trials to fully realize the clinical utility of these biomarkers, which could ultimately improve patient outcomes in the context of high-grade gliomas. This is a well-written review which had meet stringent requirements of high scientific quality and significance. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: ICH, Minimally invasive neurosurgery (MIN) , Neuroprotection & Neural repair I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Huang APH. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r364631 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-364631 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Rahmawati D. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r359383 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-359383 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Jan 2025 Dessika Rahmawati , Universitas Brawijaya/Dr. Saiful Anwar General Hospital, Malang, Indonesia Approved VIEWS 0 https://doi.org/10.5256/f1000research.176321.r359383 Dear Journal Editor I accept the review of this ... Continue reading READ ALL Dear Journal Editor I accept the review of this journal and I agree to index this journal without more revision. Thankyou Competing Interests: No competing interests were disclosed. Reviewer Expertise: In essence, this review is crucial because it not only advances our understanding of gliomas at a molecular level but also has the potential to translate these findings into tangible benefits for patients. It represents a bridge between cutting-edge research and clinical application, with the ultimate goal of improving outcomes for individuals affected by this challenging disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Rahmawati D. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r359383 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-359383 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 15 Jul 2024 Views 0 Cite How to cite this report: Rahmawati D. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.165992.r340043 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v1#referee-response-340043 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 12 Dec 2024 Dessika Rahmawati , Universitas Brawijaya/Dr. Saiful Anwar General Hospital, Malang, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.165992.r340043 Feedback: Ensure consistent use of terminology (e.g., "miRNA" vs. "mRNA" in the context of gliomas). Citations: Verify all citations for accuracy and completeness. For instance, ensure the references like "1" and "2" directly correspond ... Continue reading READ ALL Feedback: Ensure consistent use of terminology (e.g., "miRNA" vs. "mRNA" in the context of gliomas). Citations: Verify all citations for accuracy and completeness. For instance, ensure the references like "1" and "2" directly correspond to listed sources. Methodology: Your methods section is detailed, but consider adding a flowchart or diagram to visually represent the selection and inclusion process. Results and Discussion: If possible, include a brief overview of key findings from the included studies. Highlight any significant miRNA biomarkers identified and their clinical implications. Overall, this article provides valuable insights into the role of miRNAs in glioma diagnosis and prognosis. It would be beneficial to ensure that all sections are seamlessly integrated, with a clear connection between the background, methods, results, and conclusions. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: In essence, this review is crucial because it not only advances our understanding of gliomas at a molecular level but also has the potential to translate these findings into tangible benefits for patients. It represents a bridge between cutting-edge research and clinical application, with the ultimate goal of improving outcomes for individuals affected by this challenging disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Rahmawati D. Reviewer Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.165992.r340043 ) The direct URL for this report is: https://f1000research.com/articles/13-796/v1#referee-response-340043 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 15 Jan 2025 Renindra Ananda Aman , Department of Neurosurgery, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia 15 Jan 2025 Author Response 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the ... Continue reading 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 15 Jan 2025 Renindra Ananda Aman , Department of Neurosurgery, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia 15 Jan 2025 Author Response 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the ... Continue reading 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 15 Jul 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 15 Jan 25 read read Version 1 15 Jul 24 read Dessika Rahmawati , Universitas Brawijaya/Dr. Saiful Anwar General Hospital, Malang, Indonesia Abel Po-Hao Huang , National Taiwan University Hospital, Taipei, Taiwan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Huang A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Feb 2025 | for Version 2 Abel Po-Hao Huang , National Taiwan University Hospital, Taipei, Taiwan 0 Views copyright © 2025 Huang A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This article indicates that specific miRNAs, such as miR-221, miR-222, and miR-21, are associated with poor prognosis and could serve as valuable indicators of disease progression. The article emphasizes the need for further validation through extensive clinical trials to fully realize the clinical utility of these biomarkers, which could ultimately improve patient outcomes in the context of high-grade gliomas. This is a well-written review which had meet stringent requirements of high scientific quality and significance. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise ICH, Minimally invasive neurosurgery (MIN) , Neuroprotection & Neural repair I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Huang APH. Peer Review Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r364631) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-364631 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Rahmawati D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Jan 2025 | for Version 2 Dessika Rahmawati , Universitas Brawijaya/Dr. Saiful Anwar General Hospital, Malang, Indonesia 0 Views copyright © 2025 Rahmawati D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Dear Journal Editor I accept the review of this journal and I agree to index this journal without more revision. Thankyou Competing Interests No competing interests were disclosed. Reviewer Expertise In essence, this review is crucial because it not only advances our understanding of gliomas at a molecular level but also has the potential to translate these findings into tangible benefits for patients. It represents a bridge between cutting-edge research and clinical application, with the ultimate goal of improving outcomes for individuals affected by this challenging disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Rahmawati D. Peer Review Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.176321.r359383) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-796/v2#referee-response-359383 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Rahmawati D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 12 Dec 2024 | for Version 1 Dessika Rahmawati , Universitas Brawijaya/Dr. Saiful Anwar General Hospital, Malang, Indonesia 0 Views copyright © 2024 Rahmawati D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Feedback: Ensure consistent use of terminology (e.g., "miRNA" vs. "mRNA" in the context of gliomas). Citations: Verify all citations for accuracy and completeness. For instance, ensure the references like "1" and "2" directly correspond to listed sources. Methodology: Your methods section is detailed, but consider adding a flowchart or diagram to visually represent the selection and inclusion process. Results and Discussion: If possible, include a brief overview of key findings from the included studies. Highlight any significant miRNA biomarkers identified and their clinical implications. Overall, this article provides valuable insights into the role of miRNAs in glioma diagnosis and prognosis. It would be beneficial to ensure that all sections are seamlessly integrated, with a clear connection between the background, methods, results, and conclusions. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests No competing interests were disclosed. Reviewer Expertise In essence, this review is crucial because it not only advances our understanding of gliomas at a molecular level but also has the potential to translate these findings into tangible benefits for patients. It represents a bridge between cutting-edge research and clinical application, with the ultimate goal of improving outcomes for individuals affected by this challenging disease. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 15 Jan 2025 Renindra Ananda Aman, Department of Neurosurgery, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia 1.⁠ ⁠We have make sure that terminology miRNA is the one that we use in our study, not mRNA 2.⁠ ⁠At method section, we add one sentence that explain the flow chart will be displayed at result section. 3.⁠ ⁠From result until discussion section, we have adjust and verify all citations used in our study 4.⁠ ⁠At discussion section, one paragraph has been added explaining brief overview and highlight of significant miRNA View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Rahmawati D. Peer Review Report For: Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review [version 2; peer review: 2 approved] . F1000Research 2025, 13 :796 ( https://doi.org/10.5256/f1000research.165992.r340043) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-796/v1#referee-response-340043 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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