Table 4.
Recent clinical studies that evaluated miRNAs as potential biomarkers in GBM.
| Biomarker | Study Title | Cancer Types | Patients (n) (Cases/Controls) | Controls | Biofluid | Method | Alterations | Results | References |
|---|---|---|---|---|---|---|---|---|---|
| miR-7 | Dynamic expression of 11 miRNAs in 83 consecutive primary and corresponding recurrent glioblastoma: correlation to treatment, time to recurrence, overall survival and MGMT methylation status | GBM | 83 | Recurrent GBM vs primary GBM | FFPE tissues | qRT-PCR | Downregulation | Significant change in the expression of miR-7, miR-9, miR-21, miR-26b, mirR-124a, miR-199a, and let-7f in the recurrent tumor compared to the primary tumor. In the recurrent tumor, miR-15b, let-7d, and let-7f significantly changed compared to both treatment options. |
[183] |
| miR-10b | Human glioma growth is controlled by microRNA-10b | GBM | 258 | NA | Tissue | TCGA tumor tissue data analysis | Upregulation | miR-10b is upregulated in both low-grade and high-grade gliomas. High miR-10 levels associated with much shorter patient survival compared with the low miR-10 expressors. miR-10b expression correlated with the expression of genes that belong to “G1/S transition”, “G2/M transition”, “S phase”, and “M phase of mitotic cell cycle” bioterms. |
[184,185] |
| miR-15b miR-21 |
miR-15b and miR-21 as Circulating Biomarkers for Diagnosis of Glioma | GBM | 16/30 | Neurologic disorders | Serum | qRT-PCR | Downregulation | Elevated miR-15b and miR-21 were detected in the blood of GBM patients. miR-15b and miR-21 showed high sensitivity (90%) and specificity (100%) in distinguishing glioma patients from non-glioma patients |
[174] |
| miR-15b miR-23a miR-133a miR-150 miR-197 miR-497 miR-548b-5p |
Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytoma | Newly diagnosed Astrocytomas (WHO grades III-IV) |
33/80 | Healthy | Serum | qRT-PCR | Downregulation | Seven miRNAs were significantly decreased in grades II–IV patients (p < 0.001), and all seven miRNA panels exhibited a high sensitivity (88.00%) and specificity (97.87%) in predicting malignant astrocytomas and were downregulated in tumor tissues compared to normal tissues. Furthermore, these miRNAs in serum were markedly elevated after operation (p < 0.001). | [173] |
| miR-21 miR-128 miR-342-3p |
Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma | GBM | 10/10 | Healthy | Plasma | qRT-PCR | miR-21 Upregulation miR-128 Downregulation miR-342-3 Downregulation |
miR-21, miR-128, and miR-342-3p were significantly altered in GBM patients compared to normal controls but not in other brain tumors like meningioma or pituitary adenoma. Additionally, miR-128 and miR-342-3p were positively correlated with histopathological grades of glioma. | [171] |
| miR-30c | GBM | 53 | 53 paired GBM tissues and adjacent normal brain tissues | Tissue | qRT-PCR | Downregulation | The expression of miR-30c was significantly downregulated in GBM tissues compared to in normal tissues. The miR-30c decrease was more pronounced in high-grade GBM tissues compared to in low-grade tissues. |
[186,187] | |
| miR-125b-2 | MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis | GBM | N/A | Normal human brain tissues obtained from patients with severe TBI who needed post-trauma surgery | Tissue | qRT-PCR | Downregulation | miR-125b-2 expression was upregulated in GBM tissues and the corresponding stem cells (GBMSCs), which conferred resistance to TMZ. | [188] |
| miR-128 | Serum microRNA-128 as a biomarker for diagnosis of glioma | GBM | 61/53 | Healthy | Serum | qRT-PCR | Downregulation | The expression of miR-128 was notably reduced in preoperative glioma serum compared to both normal controls and meningioma serum samples (both p < 0.001). After surgery, miR-128 expression significantly increased (p < 0.001), but it did not reach normal levels (p < 0.001). Additionally, low miR-128 levels in serum and tissue were associated with a high pathological grade and low KPS | [172] |
| miR-128 miR-342-3p |
A specific miRNA signature in the peripheral blood of glioblastoma patients | GBM | 20/20 | Healthy | Blood | qRT-PCR | miR-128 Upregulation miR-342-3 Downregulation |
Among 1158 tested miRNAs, 52 exhibited significant deregulations.Only miR-128 (upregulated) and miR-342-3p (downregulated) remained significant after correction for multiple testing. | [181] |
| miR-130b | MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells | Astrocytic gliomas | 12 | 4 on-neoplastic brain specimens as controls | Fresh tissues | qRT-PCR | Upregulation | The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non-neoplastic brain specimens | [189] |
| miR-181c miR-181d |
Clinical Relevance and Interplay between miRNAs in Influencing Glioblastoma Multiforme Prognosis | GBM | 112 | FFPE | qRT-PCR | Downregulation | The OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis | [190] | |
| miR-181c miR-181d miR-21 miR-195 miR-196b miR-648 miR-767.3 |
Identification of MGMT Downregulation Induced by miRNA in Glioblastoma and Possible Effect on Temozolomide Sensitivity | GBM | 112 | FFPE | qRT-PCR | Upregulation Downregulation |
miR-21 and miR-196b were upregulated and miR-767.3 was downregulated in GBM. Low expression of miR-181c, miR-195, miR-648, and miR-767.3p was associated with positive MGMT IHC. A significant association was found between unmethylated cases and the low expression of miR-181d and miR-648 and between methylated cases and the low expression of miR-196b. Negative MGMT IHC; in methylated patients and in the cases with miR-21, miR-196b was associated with a better OS. |
[191] | |
| miR-182 | Potential Diagnostic and Prognostic Value of Plasma Circulating MicroRNA-182 in Human Glioma | GBM | 39/54 | Healthy | Plasma | qRT-PCR | Upregulation | miR-182 in glioma patients was higher than that in healthy controls, which was significantly associated with the KPS score and WHO grade. | [178] |
| miR-183 | Up-regulation of microRNA-183 promotes cell proliferation and invasion in glioma by directly targeting NEFL | GBM | 44 | 44 human astrocytoma samples and 20 normal brain tissues | Tissue | QRT-PCR | Upregulation | miR-183 was significantly upregulated in astrocytoma tissues and glioblastoma cell lines. NEFL as a novel target gene of miR-183. The expression levels of NEFL are inversely correlated with those of miR-183 in human astrocytoma clinical specimens |
[192] |
| miR-203 | MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression | GBM (TMZ-resistant and non-resistant patients) | 192 | 96 patients showing a response (CR and PR) to TMZ treatment and 96 patients showing no response (SD and PD). | FFPE tissues and serum | qRT-PCR | Downregulation | miR-203 was downregulated by lncRNA MALAT1. LncRNA MALAT1 inhibition re-sensitized TMZ-resistant cells through upregulating miR-203 and downregulating TS expression |
[193] |
| miR-205 | Downregulation of serum microRNA-205 as a potential diagnostic and prognostic biomarker for human glioma | GBM | 27/45 | Healthy | Serum | qRT-PCR | Downregulation | Serum miR-205 levels were significantly lower in patients with glioma than in healthy controls and demonstrated a stepwise decrease with ascending pathological grades and KPS scores. Higher miR-205 serum levels were correlated with a longer OS. | [179] |
| miR-210 | Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma | GBM | 42/50 | Healthy | Serum | qRT-PCR | Upregulation | [175] | |
| miR-221 miR-222 |
Clinical impact of circulating oncogenic miRNA-221 and MiRNA-222 in glioblastoma multiform | GBM | 20/20 | Healthy | Serum | qRT-PCR | Upregulation | miR-221 and -222 were significantly increased in GBM cases as compared to healthy individuals. Higher levels of miR-221 and miR-222 were correlated with PD and patients with a worse PFS and OS. |
[182] |
| miR-320a | miR-320a functions as a suppressor for gliomas by targeting SND1 and β-catenin, and predicts the prognosis of patients | Astrocytic gliomas | 120 | Surgical specimens of 120 astrocytic gliomas and 20 nontumoral brain tissues | FFPE tissues | ISH | Downregulation | miR-320a expression was decreased in human glioma tissues and cell lines. Reduced miR-320a expression was inversely correlated with glioma grades and Ki-67 indexes but positively correlated with patients’ survival. |
[194] |
| miR-339-5p miR-21-5p mR-92b-3p miR-182-5p |
Simultaneous miRNA and mRNA transcriptome profiling of glioblastoma samples reveals a novel set of OncomiR candidates and their target genes | GBM | 50 | 50 GBM tissue samples and 7 healthy tissue samples | Tissue samples | qRT-PCR | Upregulation | miR-339-5p, miR-21-5p, miR-92b-3p, and miR-182-5p were found to be significantly upregulated in GBM samples. An increased miR-21 expression level was correlated with an older age at diagnosis in GBM. |
[195] |
| miR-454-3p | Plasma miR-454-3p as a potential prognostic indicator in human glioma | GBM | 22/70 | Healthy | Plasma | qRT-PCR | Upregulation | The levels of miR-454-3p were higher in high-grade gliomas than in low-grade gliomas. The post-operative plasma levels of miR-454-3p were downregulated significantly compared to the pre-operative levels. High miR-454-3p levels are associated with a poorer prognosis. |
[176] |
| miR-497 | A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas | GBM | 10/15 | Healthy | Serum | qRT-PCR | Downregulation | miR-497 and miR-125b serum levels were decreased depending on tumor stages, with reduced levels in GBM than in lower-grade tumors. | [177] |
| miR-519a | miR-519a enhances chemo sensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway | GBM | 48 | 24 patients with recurrent GBM treated with TMZ before the second surgery and 24 patients with primary GBM without TMZ treatment | FFPE | Downregulation | Downregulation of miR-519a and upregulation of STAT3 in recurrent GBM tissues were detected compared to primary GBM tissues. | [196,197] | |
| miR-595 | MiR-595 targeting regulation of SOX7 expression promoted cell proliferation of human glioblastoma | GBM | 8 | 8 paired human GBM tissues and the matched tumor-adjacent tissues | Tissue | QRT-PCR | Upregulation | MiR-595 expression was significantly upregulated in GBM tissues and cells. | [198,199] |
| miR-758-5p | Mir-758-5p Suppresses Glioblastoma Proliferation, Migration and Invasion by Targeting ZBTB20 | GBM | 55 | 55 paired GBM tissues and adjacent normal tissues | Tissue samples | qRT-PCR | Downregulated | miR-758-5p was significantly downregulated in GBM tissues. High miR-758-5p expression indicated an enhanced prognosis of patients with GBM. |
[200] |
| miR-146b-5p | miR-146b-5p functions as a tumor suppressor by targeting TRAF6 and predicts the prognosis of human gliomas | Astrocytic gliomas | 147 | 20 nontumoral brain tissues as controls | FFPE tissues | ISH | Downregulation | Reduced miR-146b-5p expression was inversely correlated with the grades and Ki-67 index in 147 human glioma specimens but positively correlated with patients’ survival. | [1] |
Abbreviations: CR, Complete response; FFPE, Formalin-Fixed Paraffin-Embedded; ISH, in situ hybridization; KPS, Karnofsky Performance Status; lncRNA, long noncoding RNA; miR, microRNA; N/A, not available; NEFL, neurofilament light polypeptide; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; qRT-PCR, quantitative reverse transcription polymerase chain reaction. SD, stable disease; TBI, traumatic brain injury; TS, thymidylate synthase.