Table 1.
Down-regulated miRNA in neuroblastoma (NB, Neuroblastoma; ANT, adjacent normal tissues; OS, overall survival; EFS, event-free survival).
| miRNA | Specimens | Cell line | Targets/regulators | Signaling pathway | Function | Effect of miRNA down-regulation on patient’s prognosis | Reference |
|---|---|---|---|---|---|---|---|
| miR-490-5p | 72 tumor tissues and ANTs | SH-SY5Y, SK-NSH, U343 | MYEOV | – | Down-regulated miR-490-5p levels correlate with advanced INSS stage, lymph node involvement, and poor outcome. MiR-490-5p overexpression thwarts cell proliferation, migratory capacities, invasive effects, and enhances the cell cycle arrest and apoptosis. | Poor survival | (22) |
| miR-144 | SH-SY5Y, SK-N-SH, HUVEC | MYCN | miR-144 influences proliferation, apoptosis and cisplatin resistance. | ||||
| miR-144-3p | 46 pairs of NB ANTs | SK-N-SH, SH-SY5Y, HUVEC, | HOXA7 | – | miR-144-3p repression results in the advancement of cell proliferation, cell cycle progression, and cell migration. Down-regulation of miR-144-3p level correlates with advanced tumor stage, greater carcinoma size, and lymph node metastasis. | – | (23) |
| miR-34a | 35 pediatric NB patients, 15 normal adrenal tissue | SH-SY5Y | MMP-2, MMP-14, HNF4α | – | miR-34a down-regulation increases cell proliferation, migration, and invasion. | – | (24) |
| 18 NB primary and their metastatic tissues | SH-SY5Y, IMR-32 | CD44 | – | miR-34a repression results in enhanced metastasis, proliferation, and invasion rates in NB cells. | – | (17) | |
| 32 NB and ANTs | SH-SY5Y, SK-N-SH, HUVEC | ATG5 | – | proliferation, migration, and invasion rate increase following the miR-34a repression, and the apoptosis rate diminishes. | Lower survival rate | (18) | |
| miR-183 | – | IMR-32, SH-SY5Y, SK-N-MC, SK-N-SH, HEK293, KCLB, HEF, SK-N-DZ | -/MYCN, HDAC2 | – | MYCN inhibition increases the pro-apoptotic miR-183 levels. | – | (25) |
| – | BE(2)-C, Kelly | MCM complex | – | miR-183 down-regulates the MCM complex. | – | (26) | |
| miR-323a-5p | 253 NB patients | SK-N-AS, SH-SY5Y, IMR-32, HEK293T141, CHLA-90, SK-N-BE(2), LA1-5 | CHAF1A, KIF11, INCENP, CDC25A, CCND1, FADD, E2F2 | – | These miRNAs reduce cell proliferation, cell viability, cell cycle, and tumor growth, though they increase the apoptosis rate. | – | (27) |
| miR-342-5p | AKT2, CCND1, MKNK2, BCLX | Poor OS | |||||
| miR-34b | – | SH-SY5Y, IMR-32, KELLY | DLL1 | Notch-Delta | miRNA-34b markedly down-regulates the DLL1 mRNA expression levels, arrests cell proliferation, induces neuronal differentiation in malignant NB cells. | – | (28) |
| miR-145 | – | SH-SY5Y | Bnip3 | – | miR-145 inhibition promotes mitophagy activity and subsequently increases SH-SY5Y cell survival. | – | (29) |
| miR-2110 | SEQC dataset: 498 NB patients | BE(2)-C, SKNDZ, CHLA-90, SKNFI | TSKU | – | miR-2110 overexpression induces cell differentiation and inhibits cell survival. | Poor OS and EFS | (30) |
| miR-186 | GSE62564 dataset: 498 NB patients | CHLA-136, LAN-5, CHLA-255, HEK293T | MYCN, AURKA, TGFBR1, TGFBR2, TGFβ1 | TGFβ | miR-186 lower expression levels relate to a poor prognosis in NB patients that directly correlates with NK activation markers. | Poor EFS and OS | (31) |
| let-7 | – | KELLY, BE2C, SH-SY5Y | TGF-βRI, LMO1, MYCN | – | let-7 decreases the expression levels of TGF-βRI, LMO1, and MYCN. | – | (32) |
| – | BE(2)-C, SMS-KCNR, CHLA90 | -/DFMO, LIN28B, MYCN | – | Difluoromethylornithine inhibits ornithine decarboxylase, which in turn regulates polyamines. Polyamines regulate eIF-5A, which is a modulator of the LIN28/Let-7 axis. Difluoromethylornithine reduces neurosphere formation, ATP production, and LIN28B and MYCN protein levels yet enhances let-7. | – | (33) | |
| GSE81500 dataset: 172 NB patients | BE(2)C, PA-1, IMR90, SK-N-AS, SH-SY5Y, HEK293T, SK-N-DZ, Kelly | -/MYCN | – | Genetic loss of let-7 is common in NB and is negatively associated with MYCN amplification. Down-regulation of let-7 is associated with poor outcomes. | Lower OS | (34) | |
| miR-15a/miR-16-1 | – | HTLA-230, HTLA-ER, HCT116 TP53−/− | BMI-1, p16/p53 | – | miR-15a/16-1 down-regulation enhances BMI-1 oncoprotein up-regulation, which decreases p16 tumor suppressor and increases etoposide resistance. | – | (35) |
| – | SK-N-BE(2), Shy-SY5Y, MHH-NB-11, PC3, RPMI-8266 |
Bcl2, cyclin D1, CCND1, ERK/CXCR4 | MAPK | Up-regulation of miR-15a/16-1, regulated by CXCR4, results in the repression of BCL-2 and cyclin D1. miR-15a/16-1 increases apoptosis and reduces the proliferation and survival of tumor cells. | – | (36) | |
| hsa-miR-34a-5p, has-let7 family, hsa-miR-16-5p, hsa-miR-20b-5p, hsa-miR-409-3p | – | SK-N-SH, LA-N-5, SK-N-BE | -/LMO1 | – | These miRNAs significantly diminish cell proliferation of NB cell lines. | – | (37) |
| miR-146a | – | SK-N-SH, HEK293 | BCL11A | – | miR-146a overexpression inhibits cell proliferation and increases the apoptosis rate of human NB cells. | – | (38) |
| miR-129 | 88 NB and 23 ANTs | NBSD, SK-N-SH, SK-SY-5Y, SK-N-AS, IMR-32, Neuro-2a, BEM17, NB1, Kelly, NB-1643, HEK293T |
MYO10 | – | miR-129 down-regulates MYO10 levels and then represses cell proliferation and increased chemosensitivity. | – | (39) |
| miR-1247 | 10 primary NB and the corresponding ANTs | SH-SY5Y, SK-N-SH | ZNF346 | – | miR-1247 markedly decreases cell proliferation and induces cell cycle arrest and cell death. | – | (40) |
| miR-204 | 200 NB tumors | BE(2)C, SH-SY5Y, SHEP, Kelly, SK-N-AS, SK-N-FI, IMR32 | MYCN | – | MYCN binds to the miR-204 promoter and represses miR-204 transcription. miR-204 directly binds MYCN mRNA and diminishes MYCN expression. | – | (41) |
| miR-664a-5p | – | SH-SY5Y | – | – | miR-664a-5p enhances neuronal differentiation. | – | (42) |
| miR-124 | – | M17 | β-Tubulin III, MAP2, SYN, NF-M, Nestin | – | miR-124 up-regulation increases differentiation in neuronal lineages. | – | (43) |
| miR-505-3p | – | N2a, U251 | SRSF1 | – | miR-505-3p impedes neural tumor proliferation driven by SRSF1, solely in serum-reduced condition. | – | (44) |
| miR-513 | 10 primary NB and matched ANTs | SK-N-SH, SK-N-BE2, SH-SY5Y, SK-N-AS, SK-N-DZ | GLS | – | miR-513c inhibits migration, invasion, and proliferation. | – | (45) |
| miR-205 | 28 tumor and adjacent normal tissues of NB patients | SH-SY5Y, SK-N-SH, IMR32, BE(2)-C, HUVEC |
CREB1, BCL-2, MMP9 | – | Expression of miR-205 is down-regulated in poorly differentiated NB tissues and those of advanced stage. | – | (46) |
| miR-628-3p | 22 primary NB and 21 normal tissues | KCNR, HEK293T, LAN5, SH-SY5Y, SK-N-SH | MYCN | – | miR-628-3p has a tumor-suppressor characteristic and down-regulates MYCN. | – | (47) |
| miR-17 | – | SK-N-BE(1)n, LA1-55n, KCN-83n, BE(2)-M17V, SK-N-LD, SK-N-HM, BE(2)-C, LA1-5s, SH-SY5Y, SMS-LHN, CB-JMN, SH-EP1, SMS-KCNs |
N-myc/ELAVL4 | – | miR-17 down-regulates N-myc mRNA and protein levels, while ELAVL4 up-regulates N-myc and is a competitive factor for miR-17. | – | (48) |
| miR-149 | 117 NB patients | SH-SY5Y, CHP-212, IMR-32, SK-N-SH, SK-N-AS, NB1691, LAN1, LAN5, LAN6 |
Rap1 | – | Down-regulation of miR-149 expression is associated with advanced stages of primary NB tumors and poor OS. | Poor OS | (49) |
| miR-137 | – | SH-SY5Y, SK-N-SH, MIR-32, SK-N-BE (2), normal fibroblast 3T3 cells, primary normal human astrocytes | MDR1/HDAC8 | – | HDAC8 is overexpressed in NB cells and down-regulates miR-137 levels, which further decreases MDR1 and sensitivity to doxorubicin. | – | (50) |
| 88 NB patients | N-2a, SH-SY5Y | EZH2, CLU, NGFR | – | Resveratrol induces miR-137 up-regulation and reduces EZH2 repression. EZH2 reduction results in increased CLU ad NGFR tumor suppressors. | Lower OS | (51) | |
| miR-143 | – | SH-SY5Y | -/NO, RBM3, p38 | – | RBM3 abolishes the induction of miR-143 and apoptosis. | – | (52) |
| miR-410 | 61 cases of NB and normal tissues | SK-N-BE(2), NB1691 | VEGFA/SPARC | – | Concomitant SPARC up-regulation and radiation restricts tumor growth and angiogenesis by down-regulating VEGF-A via miR-410. | – | (53) |
| miR-93-5p | – | SK-N-AS | VEGF, IL-8 | – | miR-93-5p is down-regulated in NB cells, which promotes VEGF and IL-8 and tumorigenesis. | – | (54) |
| miR-141 | – | IMR-32, SH-SY5Y, S-K-NAS, NB-1691, LAN-5, LAN-6, HEK293T | FUS | – | miR-141 up-regulation inhibits cancer proliferation, cell cycle progression, tumor growth, migration, and rises cisplatin sensitivity. | – | (55) |
| miR-497 | NRC dataset: 365 NB samples | CHLA-90, SK-N-BE(2), LA1-5s, SK-N-AS, HEK293T | WEE1, CHEK1, AKT3, BCL2, VEGFA | – | miR-497 overexpression reduces the proliferation of multiple chemoresistant NB cell lines and induced apoptosis in MYCN-amplified cell lines. Moreover, miR-497 in NB xenografts diminishes tumor growth and inhibits vascular permeabilization. | Lower progression-free survival | (56) |
| miR-451 | 37 NB and ANTs | SK−N−SH, GI−LA−N | MIF | – | miR-451 reduces cell proliferation, invasion, and migration. Reduction in miR−451 increases tumor size, dedifferentiation, lymph node metastasis, TNM stage, and remote metastases. | – | (57) |
| miR-203 | 16 NB and ANTs | SK−N−SH, SH−SY5Y | Sam68 | – | Up-regulation of miR-203 inhibits the proliferation, migration, and invasion rates. | – | (58) |
| miR-26a-5p | 200 patients with primary NB, GSE32664 dataset: 75 primary tumors | IMR5-75-shMYCN, SHEP-MYCN-ER, MYCN3, HEK293T | LIN28B/MYCN | – | MYCN overexpression reduces miR-26a-5p (not in the transcription stage), and miR-26b-5p results in LIN28B up-regulation. | Lower OS rate | (59) |
| miR-26b-5p | |||||||
| miR-337-3p | 30 primary NB cases and 21 normal dorsal ganglia | SK-N-SH, SKN-AS, SH-SY5Y, SKN-BE(2), HepG2, PC-3, HeLa, 786-O, HUVEC | MMP14, AGO2 | – | miR-337-3p inhibits the activity of MMP-14 promoter and, its nascent transcription. | Lower OS rate | (60) |
| miR-362-5p | 12 metastatic and 12 primary NB tissues | SH-SY5Y, IMR-32, HEK293 | PI3K-C2β | – | Overexpression of miR-362-5p inhibits cell proliferation, tumor growth, migration, and invasion of NB cells. | – | (61) |
| miR-659-3p | 22 bone marrow infiltrating samples, 22 primary tumor samples | HTLA-230, SH-SY5Y | CNOT1, AKT3, BCL2, THSB2, CYR61 | – | Inhibiting miR-659-3p results in over-expressed CNOT1 and down-regulated AKT3, BCL2, CYR61, and THSB2, (all involved in focal adhesion) as observed in bone marrow infiltrating NB cells. | – | (62) |
| miR-182-5p | 100 NB patients | NGP, NGP-lv-hp53, NGP-lv-mp53, SK-N-AS, SK-N-Be(2c), IMR-32, IMR-32-lv-hp53, IMR-32-lv-mp53. NGP/IMR-lv-hp53, NGP/IMR-lv-mp53 | -/p53 | – | Overexpression of miR-182-5p and miR-432-5p increases apoptosis rate and promotes neuronal differentiation. | – | (63) |
| miR-432-5p | Lower progression-free survival | ||||||
| miR-449a | Versteeg cohort: 88NB patients, Kocak cohort: 476 NB patients | BE(2)-C, SKNBE and BE(2)-M17, LAN6, KELLY | MFAP4, PKP4, TSEN15, CDK6, LEF1 | – | miR-449a impedes NB cell survival and proliferation by increasing cell differentiation and cell cycle arrest. | – | (64) |
| miR-520f | GSE16476 dataset: 237 NB patients, 3 FFPE matched pre-treatment and post-treatment | SK-N-AS | NAIP | – | miR-520f down-regulation increases NAIP levels. miR-520f levels are determined to be significantly lower in post-chemotherapy treatment. | – | (65) |
| miR-542-3p | 69 primary NB tumors | IMR-32, SHEP, SK-N-BE and WAC II, HEK293, SK-N-SH, SH-SY5Y | Survivin | – | Up-regulation of miR-542-3p in NB cells diminishes the cell viability and proliferation, induced apoptosis, and down-regulates Survivin. | Lower survival rate | (66) |