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Sekar, D. MicroRNAs in Neuroblastoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/17722 (accessed on 13 February 2026).
Sekar D. MicroRNAs in Neuroblastoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/17722. Accessed February 13, 2026.
Sekar, Durairaj. "MicroRNAs in Neuroblastoma" Encyclopedia, https://encyclopedia.pub/entry/17722 (accessed February 13, 2026).
Sekar, D. (2022, January 04). MicroRNAs in Neuroblastoma. In Encyclopedia. https://encyclopedia.pub/entry/17722
Sekar, Durairaj. "MicroRNAs in Neuroblastoma." Encyclopedia. Web. 04 January, 2022.
MicroRNAs in Neuroblastoma
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27010099

Neuroblastoma (NB) is a type of peripheral sympathetic nervous system cancer that most commonly affects children. Accumulating evidence suggested that microRNAs (miRNAs) are a class of non-coding RNAs with 19–25 nucleotides lengths and play a central role in the development of NB carcinogenesis.

Neuroblastoma Mechanism MiRNA

1. Molecular Mechanism Involved in Neuroblastoma (NB)

Several pathways are involved in the disease progression and inhibition of NB. Amplification of the N-myc gene or mutations of the p53 tumour suppressor genes is common in NB. According to studies, p53 mutations are occasionally linked to neuroblastoma growth, and tumourigenetic consequences of mutant p53 may differ from those of N-myc [1]. In addition, NB can also be caused by MTDH (metadherin) overexpression where MTDH is a transforming downstream mediator of oncogenic Ha-Ras and c-Myc’s activities. Furthermore, MTDH overexpression stimulates proliferation, invasion, cell survival and chemoresistance via activating the PI3K/Akt, nuclear factor kappaB (NFkappaB) and Wnt/beta-catenin signalling pathways [2]. MTDH also promotes metastasis by mediating tumour cell attachment to tissues. Wnt signalling is linked to tumour cell stemness and the production of stem cell markers and is a key component of chemoresistance in NB [3]. Likewise, during embryogenesis, the Ap-2 family has been identified to regulate face, limb and kidney development while also controlling differentiation and apoptosis. Endocrine processes are regulated by these proteins as well. These, when targeted, can lead to tumour progression.
In NB, the NF-κB signalling pathway has an antiapoptotic effect, while IκB kinase (IKK) is a kinase that is required for NF-κB activation. NF-κB is stimulated by IKK phosphorylation. In normal and malignant cells, NF-κB supports cell survival by inducing target genes whose products block components of the apoptotic machinery. By activating genes encoding antioxidant proteins, NF-κB can help prevent programmed necrosis. Many cancer cells, whether epithelial or hematopoietic in origin, use NF-κB to achieve resistance to anticancer drugs, radiation and death cytokines, regardless of mechanism [4]. Moreover, when receptor tyrosine kinases activate PI3K (phosphatidylinositol-3 kinase), it phosphorylates PIP2 (Phosphatidylinositol 4,5-bisphosphate) to create PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) and activates the signalling pathway in NB. PTEN dephosphorylates PIP3 and converts it to PIP2, hence inhibiting the pathway. AKT is a protein that is activated by PIP3 and regulates physiological activities [5]. Meanwhile, ATG5 is a protein that is involved in the early stages of autophagosome production, plays an important role in autophagosome maturation and is linked to chemoresistance in NB [6].

2. MiRNAs Down-Regulation in NB

Certain miRNAs that are down-regulated and play an important role in NB are discussed in a study by Ye et al. (2019), which explored the expression and the role of miR-3934-5p in neuroblastoma cell lines and tissue samples. The results revealed that miR-3934-5p was shown to be highly elevated in neuroblastoma tissues and cell lines and TP53INP1 as a direct target gene of miR-3934-5p. Thus, the overall results confirmed that down-regulation of miR-3934-5p may cause apoptosis and reduce neuroblastoma cell viability. Thus, the recent findings stipulated that miR-3934-5p/TP53INP1 axis appears to be a unique therapeutic target for neuroblastoma treatment [7]. Engrossingly, the results of Cheng et al. (2019) revealed that in NB cells, miR-34a inhibited cell proliferation, migration, invasion and autophagy while promoting death and miR-34a was found to be a direct target of ATG5 (autophagy-related gene 5). Furthermore, ATG5 restoration reduced the inhibitory effect of miR-34a on proliferation, apoptosis, migration, invasion and autophagy. Thus, these results indicated that miR-34a inhibited the progression of NB by targeting ATG5 and can be used as a novel therapeutic target in treating NB [8]. Wang et al. (2018), suggested that miR-129 and MYO10 axis-controlled neuroblastoma development and chemosensitivity. MYO10 expression was decreased by miR-129, which inhibited cell proliferation. miR129-mediated proliferation repression and chemosensitivity were dramatically improved when MYO10 was re-expressed. Thus, it was concluded that miR-129 suppressed NB growth and increased chemosensitivity by inhibiting MYO10, suggesting that it could be a promising target and logical therapy approach for NB [9]. Wu et al. (2015) suggested that miR-362-5p inhibited cell proliferation, migration and invasion of SH-SY5Y in both in vivo and in vitro conditions. This study discovered a functional relationship between miR-362-5p and PI3K-C2b expression, as well as the fact that PI3K-C2b was a direct target of miR-362-5p in NB. Hence, miR-362-5p could be a promising therapeutic option in the treatment of NB [10]. According to the evidence, miR-205 appears to play a role in tumour initiation, growth and metastasis in a variety of malignancies. In human NB tissue samples and cell lines, miR-205 expression was drastically reduced. In contrast, restoring miR-205 in NB cells inhibited cell proliferation, migration and invasion, as well as inducing cell death in vitro and reducing tumour growth in vivo. The direct target gene of miR-205 has been identified as cAMP-responsive element-binding protein 1 (CREB1). In NB cells, the expression of CREB1 and the CREB1 targets BCL-2 and MMP9 (Matrix metalloproteinase9) were drastically reduced when miR-205 was inhibited. The up-regulation of CREB1 partially reversed the inhibitory effects of miR-205 on NB cells. These findings imply that miR-205 may act as a tumour suppressor in NB via inhibiting CREB1 [11]. However, cell proliferation is inhibited by miR-338-3p, which also inhibits cell migration and invasion by causing cell cycle arrest by directly targeting PREX2a. The PTEN/Akt pathway suppressed cell proliferation, migration and invasion when PREX2a was knocked down. This research showed that miR-338-3p inhibits the PTEN/Akt pathway via down-regulating PREX2a. Therefore, this newly discovered function of miR-338-3p sheds fresh light on neuroblastoma and may lead to new therapeutic possibilities [12]. A study by Maugeri et al. (2016) on an in vivo murine neuroblastoma progression model revealed that miR-29a-3p and miR-34b-3p expression levels were found to be down-regulated [13]. 

3. MiRNAs Up-Regulation in NB

Certain miRNAs that are up-regulated in NB disease and progression are discussed in this section. Overexpression of miR-380-5p, in combination with activated HRAS (Harvey Rat Sarcoma virus) oncoprotein, has been shown to transform primary cells, block oncogene-induced senescence and form tumours in mice, whereas inhibition of endogenous miR380-5p in neuroblastoma cells resulted in p53 induction and extensive apoptotic cell death [14]. Furthermore, overexpression of miR-15a, miR-15b, or miR-16 resulted in a considerable reduction in MYCN mRNA and N-Myc protein levels. In NB cells, however, inhibiting miR significantly increased MYCN mRNA and N-Myc protein levels, as well as mRNA half-life. In addition, enhanced expression of miR-15a, miR-15b and miR-16 inhibited NB cell proliferation, migration and invasion. These findings demonstrate that miR-15a, miR-15b and miR-16 target MYCN to decrease tumour growth in NB. As a result, these miRs (miR-15a, miR-15b, or miR-16) could be evaluated as prospective NB therapy targets [14]. MiR-145 is well-known for its role as a tumour suppressor in a variety of cancers. Hence, Zhao et al.’s (2020) goal was to look at miR-145 as a potential tumour suppressive effect and mechanisms in high-risk neuroblastoma. In SH-SY-5Y cells, overexpression of miR-145 lowered cell viability and enhanced apoptosis. In SH-SY-5Y cells, it was discovered that MTDH (Metadherin) was a direct target for miR-145. Thus, their results revealed that low miR-145 expression is linked to a poor prognosis in NB patients and that overexpression of miR-145 inhibits NB cell proliferation by down-regulating MTDH, suggesting that miR-145 could be a target for the development of a microRNA-based NB therapy [15]. A study by Gao et al. (2014) aimed to investigate the significant role and mechanism of miR-200a in neuroblastoma. Overexpression of miR-200a in neuroblastoma cells lowered cell viability and suppressed tumour growth in mice xenografts. It was discovered that AP-2γ to be a novel target for miR-200a. As a result, miR-200a decreases AP-2γ mRNA and protein expression by targeting its 3’UTR. This research discovered that miR-200a could be used as a therapeutic target in treating neuroblastoma by direct targeting AP-2γ [16]. A study by Wu et al. (2018) explored the role and biological process of miR-1247 in NB in vitro conditions. ZNF346 (Zinc Finger Protein 346) was found to be a target of miR-1247, and its expression could be down-regulated by miR-1247 overexpression. Thus, the study confirmed that miR-1247 is directly targeted to reduce ZNF346 expression and, hence, decrease the progression of NB, suggesting that it could be a new therapeutic target for NB [17]. Mao et al. (2019) suggested that in NB cells, the overexpression of miR-149 decreased cell proliferation and colony formation while promoting cell death and Dox (doxorubicin) chemosensitivity. MiR-149 also targets cell division cycle 42 (CDC42) and B-cell lymphoma 2 (BCL2). CDC42 and BCL2 mRNA levels were also raised in NB tissues and cells, and restoring CDC42 or BCL2 reduced miR-149’s regulatory influence on NB progression. Thus, the study concluded that miR-149 inhibited cell proliferation and increased Dox chemosensitivity in NB through modulating CDC42 and BCL2, opening up a new therapy option for NB [18].
Zhou et al. (2020) used a nude mouse xenograft model to assess the effect of tumour growth with miR-429 overexpression. IKK mRNA on binding with miR-429 inhibits its role, whereas miR-429 overexpression was found to reduce neuroblastoma growth in a nude mice xenograft model. Therefore, these findings suggested that miR-429 could be a potential target for neuroblastoma treatment by inhibiting cell proliferation, migration and invasion via the NF-κB pathway [19]. Li et al. (2019) confirmed that miR-34a and hepatocyte nuclear factor 4α (HNF4α) expressions in juvenile neuroblastoma tissues. In SH-SY5Y cells, overexpression of miR-34a or knockdown of HNF4α may result in decreased cell proliferation, migration, invasion and MMP-2 and MMP-14 production. It was found that overexpression of HNF4α might reverse the inhibitory effect of miR-34a on SH-SY5Y cell proliferation, migration and invasion. Thus, this study concluded that overexpression of miR-34a, which targets HNF4α, can inhibit SH-SY5Y cells from proliferating, migrating and invading [20]. In NB tissues, it was discovered that miR-203 overexpression decreased the proliferation, migration and invasion of these two cell lines (SK-N-SH and SH-SY5Y NB cells) via binding to the 3’ untranslated region of Sam68. Therefore, the results of this study reported that miR-203/Sam68 could be used as a potential new diagnostic or therapeutic target for NB treatment [21]. Furthermore, Zhang et al. (2012) demonstrated that in both in vivo and in vitro conditions, the overexpression of miR-9 inhibited SH-SY5Y and SK-N-SH cell invasion, metastasis and angiogenesis. NB cells migration, invasion and angiogenesis were prevented by anti-miR-9 or by MMP-14 knockdown. These findings suggest that miR-9 inhibits neuroblastoma invasion, metastasis and angiogenesis by suppressing MMP-14 production via the 3’-UTR binding site [22]. These findings suggested that miRNA inhibition could be considered as a target for NB treatment. However, the knowledge of the role of miRNA inhibition in NB is still very deficient; thus, due to the limited number and scope, more research is required to know the molecular and signalling pathways of NB.

References

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  2. Hu, G.; Wei, Y.; Kang, Y. The multifaceted role of MTDH/AEG-1 in cancer progression. Clin. Cancer Res. 2009, 15, 5615–5620.
  3. Becker, J.; Wilting, J. WNT Signaling in Neuroblastoma. Cancers 2019, 11, 1013.
  4. Liu, A.M.; Wong, Y.H. Mu-opioid receptor-mediated phosphorylation of IkappaB kinase in human neuroblastoma SH-SY5Y cells. Neurosignals 2005, 14, 136–142.
  5. Carnero, A.; Paramio, J.M. The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. Front. Oncol. 2014, 4, 252.
  6. Belounis, A.; Nyalendo, C.; Le Gall, R.; Imbriglio, T.V.; Mahma, M.; Teira, P.; Beaunoyer, M.; Cournoyer, S.; Haddad, E.; Vassal, G.; et al. Autophagy is associated with chemoresistance in neuroblastoma. BMC Cancer 2016, 16, 891.
  7. Ye, W.; Liang, F.; Ying, C.; Zhang, M.; Feng, D.; Jiang, X. Downregulation of microRNA-3934-5p induces apoptosis and inhibits the proliferation of neuroblastoma cells by targeting TP53INP1. Exp. Ther. Med. 2019, 18, 3729–3736.
  8. Cheng, X.; Xu, Q.; Zhang, Y.; Shen, M.; Zhang, S.; Mao, F.; Li, B.; Yan, X.; Shi, Z.; Wang, L.; et al. miR-34a inhibits progression of neuroblastoma by targeting autophagy-related gene 5. Eur. J. Pharmacol. 2019, 850, 53–63.
  9. Wang, X.; Li, J.; Xu, X.; Zheng, J.; Li, Q. miR-129 inhibits tumor growth and potentiates chemosensitivity of neuroblastoma by targeting MYO10. Biomed. Pharmacother. 2018, 103, 1312–1318.
  10. Wu, K.; Yang, L.; Chen, J.; Zhao, H.; Wang, J.; Xu, S.; Huang, Z. miR-362-5p inhibits proliferation and migration of neuroblastoma cells by targeting phosphatidylinositol 3-kinase-C2β. FEBS Lett. 2015, 589, 1911–1919.
  11. Chen, S.; Jin, L.; Nie, S.; Han, L.; Lu, N.; Zhou, Y. miR-205 Inhibits Neuroblastoma Growth by Targeting cAMP-Responsive Element-Binding Protein 1. Oncol. Res. 2018, 26, 445–455.
  12. Chen, X.; Pan, M.; Han, L.; Lu, H.; Hao, X.; Dong, Q. miR-338-3p suppresses neuroblastoma proliferation, invasion and migration through targeting PREX2a. FEBS Lett. 2013, 587, 3729–3737.
  13. Maugeri, M.; Barbagallo, D.; Barbagallo, C.; Banelli, B.; Di Mauro, S.; Purrello, F.; Magro, G.; Ragusa, M.; Di Pietro, C.; Romani, M.; et al. Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma. Oncotarget 2016, 7, 83330–83341.
  14. Chava, S.; Reynolds, C.P.; Pathania, A.S.; Gorantla, S.; Poluektova, L.Y.; Coulter, D.W.; Gupta, S.C.; Pandey, M.K.; Challagundla, K.B. miR-15a-5p, miR-15b-5p, and miR-16-5p inhibit tumor progression by directly targeting MYCN in neuroblastoma. Mol. Oncol. 2020, 14, 180–196.
  15. Zhao, J.; Zhou, K.; Ma, L.; Zhang, H. MicroRNA-145 overexpression inhibits neuroblastoma tumorigenesis in vitro and in vivo. Bioengineered 2020, 11, 219–228.
  16. Haug, B.H.; Henriksen, J.R.; Buechner, J.; Geerts, D.; Tømte, E.; Kogner, P.; Martinsson, T.; Flægstad, T.; Sveinbjørnsson, B.; Einvik, C. MYCN-regulated miRNA-92 inhibits secretion of the tumor suppressor DICKKOPF-3 (DKK3) in neuroblastoma. Carcinogenesis 2011, 32, 1005–1012.
  17. Gao, S.L.; Wang, L.Z.; Liu, H.Y.; Liu, D.L.; Xie, L.M.; Zhang, Z.W. miR-200a inhibits tumor proliferation by targeting AP-2γ in neuroblastoma cells. Asian Pac. J. Cancer Prev. 2014, 15, 4671–4676.
  18. Zhou, X.; Lu, H.; Li, F.; Hao, X.; Han, L.; Dong, Q.; Chen, X. MicroRNA-429 inhibits neuroblastoma cell proliferation, migration and invasion via the NF-κB pathway. Cell Mol. Biol. Lett. 2020, 25, 5.
  19. Wu, T.; Lin, Y.; Xie, Z. MicroRNA-1247 inhibits cell proliferation by directly targeting ZNF346 in childhood neuroblastoma. Biol. Res. 2018, 51, 13.
  20. Zhao, D.; Tian, Y.; Xiao, A.; Shi, T.; Li, P.; Wang, L.; Zhang, M. MicroRNA-203 inhibits the malignant progression of neuroblastoma by targeting Sam68. Mol. Med. Rep. 2015, 12, 5554–5560.
  21. Li, Z.; Chen, H. miR-34a inhibits proliferation, migration and invasion of paediatric neuroblastoma cells via targeting HNF4α. Artif. Cells Nanomed. Biotechnol. 2019, 47, 3072–3078.
  22. Zhang, H.; Qi, M.; Li, S.; Qi, T.; Mei, H.; Huang, K.; Zheng, L.; Tong, Q. microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells. Mol. Cancer Ther. 2012, 11, 1454–1466.
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Subjects: Biochemistry & Molecular Biology
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