Skip to main content
Log in

The roles of microRNAs in neuroblastoma

  • Review article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and displays remarkable heterogeneity in clinical behaviors, ranging from spontaneous regression to rapid progression or resistance to multimodal treatment. Recent evidence has shown that microRNAs (miRNAs), a class of small non-coding RNAs, are involved in tumor development and progression. This article aimed to review recent advances in investigating the roles of miRNAs in NB.

Methods

We searched the PubMed/MEDLINE database for articles about the expression profile, functions and target genes of miRNAs in NB.

Results

We reviewed the most recent evidence regarding the functional roles of oncogenic and tumor suppressive miRNAs in NB and application of novel miRNA-based methods for diagnostic, prognostic and therapeutic purposes.

Conclusions

Deregulation of miRNAs is associated with the development and progression of NB, suggesting that miRNAs may serve as novel targets for the treatment of high-risk NB patients. However, their precise functions and underlying mechanisms still warrant further studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Stallings RL. MicroRNA involvement in the pathogenesis of neuroblastoma: potential for microRNA mediated therapeutics. Curr Pharm Des 2009;15:456–462.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203–216.

    Article  CAS  PubMed  Google Scholar 

  3. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am 2010;24:65–86.

    Article  PubMed  Google Scholar 

  4. Park JR, Bagatell R, London WB, Maris JM, Cohn SL, Mattay KM, et al. Children’s Oncology Group’s 2013 blueprint for research: Neuroblastoma. Pediatr Blood Cancer 2013;60:985–993.

    Article  PubMed  Google Scholar 

  5. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75:843–854.

    Article  CAS  PubMed  Google Scholar 

  6. Schwarzenbacher D, Balic M, Pichler M. The role of microRNAs in breast cancer stem cells. Int J Mol Sci 2013;14:14712–14723.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Xie Y, Todd NW, Liu Z, Zhan M, Fang H, Peng H, et al. Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. Lung Cancer 2010;67:170–176.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Gandellini P, Giannoni E, Casamichele A, Taddei ML, Callari M, Piovan C, et al. miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts. Antioxid Redox Signal 2013 Sep 17.

    Google Scholar 

  9. Di Leva G, Croce CM. The role of microRNAs in the tumorigenesis of ovarian cancer. Front Oncol 2013;3:153.

    PubMed Central  PubMed  Google Scholar 

  10. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215–233.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 2009;10:126–139.

    Article  CAS  PubMed  Google Scholar 

  12. Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell 2008;13:496–506.

    Article  CAS  PubMed  Google Scholar 

  13. Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol 2009;4:199–227.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Mestdagh P, Fredlund E, Pattyn F, Schulte JH, Muth D, Vermeulen J, et al. MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene 2010;29:1394–1404.

    Article  CAS  PubMed  Google Scholar 

  15. Mestdagh P, Boström AK, Impens F, Fredlund E, Van Peer G, De Antonellis P, et al. The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma. Mol Cell 2010;40:762–773.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Schulte JH, Marschall T, Martin M, Rosenstiel P, Mestdagh P, Schlierf S, et al. Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 2010;38:5919–5928.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. De Brouwer S, Mestdagh P, Lambertz I, Pattyn F, De Paepe A, Westermann F, et al. Dickkopf-3 is regulated by the MYCNinduced miR-17-92 cluster in neuroblastoma. Int J Cancer 2012;130:2591–2598.

    Article  PubMed  Google Scholar 

  18. Chen Y, Tsai YH, Fang Y, Tseng SH. Micro-RNA-21 regulates the sensitivity to cisplatin in human neuroblastoma cells. J Pediatr Surg 2012;47:1797–1805.

    Article  PubMed  Google Scholar 

  19. Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A, et al. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 2010;16:1134–1140.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Huang TC, Chang HY, Chen CY, Wu PY, Lee H, Liao YF, et al. Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR. FEBS Lett 2011;585: 3582–3586.

    Article  CAS  PubMed  Google Scholar 

  21. Xin C, Buhe B, Hongting L, Chuanmin Y, Xiwei H, Hong Z, et al. MicroRNA-15a promotes neuroblastoma migration by targeting reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and regulating matrix metalloproteinase-9 expression. FEBS J 2013;280:855–866.

    CAS  PubMed  Google Scholar 

  22. Tivnan A, Tracey L, Buckley PG, Alcock LC, Davidoff AM, Stallings RL. MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma. BMC Cancer 2011;11:33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Cole KA, Attiyeh EF, Mosse YP, Laquaglia MJ, Diskin SJ, Brodeur GM, et al. A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res 2008;6:735–742.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Chen Y, Tsai YH, Tseng SH. Inhibition of cyclin-dependent kinase 1-induced cell death in neuroblastoma cells through the microRNA-34a-MYCN-survivin pathway. Surgery 2013;153:4–16.

    Article  PubMed  Google Scholar 

  25. Gattolliat CH, Thomas L, Ciafrè SA, Meurice G, Le Teuff G, Job B, et al. Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma. Br J Cancer 2011;105:1352–1361.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Schulte JH, Marschall T, Martin M, Rosenstiel P, Mestdagh P, Schlierf S, et al. Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 2010;38:5919–5928.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Bray I, Tivnan A, Bryan K, Foley NH, Watters KM, Tracey L, et al. MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma. Cancer Lett 2011;303:56–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Buechner J, Tømte E, Haug BH, Henriksen JR, Løkke C, Flægstad T, et al. Br J Cancer 2011;105:296–303.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Afanasyeva EA, Mestdagh P, Kumps C, Vandesompele J, Ehemann V, Theissen J, et al. MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. Cell Death Differ 2011;18:974–984.

    Article  CAS  PubMed  Google Scholar 

  30. Lee JJ, Drakaki A, Iliopoulos D, Struhl K. MiR-27b targets PPAR[gamma] to inhibit growth, tumor progression and the inflammatory response in neuroblastoma cells. Oncogene 2012;31:3818–3825.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Chakrabarti M, Banik NL, Ray SK. miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo. Exp Cell Res 2013;319:1575–1585.

    Article  CAS  PubMed  Google Scholar 

  32. Althoff K, Beckers A, Odersky A, Mestdagh P, Köster J, Bray IM, et al. MiR-137 functions as a tumor suppressor in neuroblastoma by downregulating KDM1A. Int J Cancer 2013;133:1064–1073.

    Article  CAS  PubMed  Google Scholar 

  33. Ryan J, Tivnan A, Fay J, Bryan K, Meehan M, Creevey L, et al. MicroRNA-204 increases sensitivity of neuroblastoma cells to cisplatin and is associated with a favourable clinical outcome. Br J Cancer 2012;107:967–976.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Foley NH, Bray I, Watters KM, Das S, Bryan K, Bernas T, et al. MicroRNAs 10a and 10b are potent inducers of neuroblastoma cell differentiation through targeting of nuclear receptor corepressor 2. Cell Death Differ 2011;18:1089–1098.

    Article  CAS  PubMed  Google Scholar 

  35. Qiao J, Lee S, Paul P, Theiss L, Tiao J, Qiao L, et al. miR-335 and miR-363 regulation of neuroblastoma tumorigenesis and metastasis. Surgery 2013;154:226–233.

    Article  PubMed  Google Scholar 

  36. Lynch J, Fay J, Meehan M, Bryan K, Watters KM, Murphy DM, et al. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway. Carcinogenesis 2012;33:976–985.

    Article  CAS  PubMed  Google Scholar 

  37. Slaby O. MiR-190 leads to aggressive phenotype of neuroblastoma through indirect activation of TrkB pathway. Med Hypotheses 2013;80:325–326.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang H, Qi M, Li S, Qi T, Mei H, Huang K, et al. microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells. Mol Cancer Ther 2012;11:1454–1466.

    Article  PubMed  Google Scholar 

  39. Zhang H, Pu J, Qi T, Qi M, Yang C, Li S, et al. MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene 2012 Dec 10.

    Google Scholar 

  40. Bienertova-Vasku J, Mazanek P, Hezova R, Curdova A, Nekvindova J, Kren L, et al. Extension of microRNA expression pattern associated with high-risk neuroblastoma. Tumor Biol 2013;34:2315–2319.

    Article  CAS  Google Scholar 

  41. Guo J, Dong Q, Fang Z, Chen X, Lu H, Wang K, et al. Identification of miRNAs that are associated with tumor metastasis in Neuroblastoma. Cancer Biol Ther 2010;9:446–452.

    Article  CAS  PubMed  Google Scholar 

  42. Northcott PA, Fernandez-L A, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y, et al. The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res 2009;69:3249–3255.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Valdora F, Banelli B, Stigliani S, Pfister SM, Moretti S, Kool M, et al. Epigenetic silencing of DKK3 in medulloblastoma. Int J Mol Sci 2013;14:7492–7505.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Buechner J, Henriksen JR, Haug BH, Tømte E, Flaegstad T, Einvik C. Inhibition of mir-21, which is up-regulated during MYCN knockdown-mediated differentiation, does not prevent differentiation of neuroblastoma cells. Differentiation 2011;81:25–34.

    Article  CAS  PubMed  Google Scholar 

  45. Lin RJ, Lin YC, Chen J, Kuo HH, Chen YY, Diccianni MB, et al. microRNA signature and expression of Dicer and Drosha can predict prognosis and delineate risk groups in neuroblastoma. Cancer Res 2010;70:7841–7850.

    Article  CAS  PubMed  Google Scholar 

  46. De Preter K, Mestdagh P, Vermeulen J, Zeka F, Naranjo A, Bray I, et al. miRNA Expression profiling enables risk stratification in archived and fresh neuroblastoma tumor samples. Clin Cancer Res 2011;17:7684–7692.

    Article  PubMed  Google Scholar 

  47. Buckley PG, Alcock L, Bryan K, Bray I, Schulte JH, Schramm A, et al. Chromosomal and microRNA expression patterns reveal biologically distinct subgroups of 11q-neuroblastoma. Clin Cancer Res 2010;16:2971–2978.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Chakrabarti M, Ai W, Banik NL, Ray SK. Overexpression of miR-7-1 Increases efficacy of green tea polyphenols for induction of apoptosis in human malignant neuroblastoma SHSY5Y and SK-N-DZ cells. Neurochem Res 2013;38:420–432.

    Article  CAS  PubMed  Google Scholar 

  49. Chen H, Shalom-Feuerstein R, Riley J, Zhang SD, Tucci P, Agostini M, et al. miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro. Biochem Biophys Res Commun 2010;394:921–927.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang H, Li Y, Lai M. The microRNA network and tumor metastasis. Oncogene 2009;29:937–948.

    Article  PubMed  Google Scholar 

  51. Kos A, Olde Loohuis NF, Wieczorek ML, Glennon JC, Martens GJ, Kolk SM, et al. A potential regulatory role for intronic microRNA-338-3p for its host gene encoding apoptosisassociated tyrosine kinase. PLoS One 2012;7:e31022.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Tivnan A, Orr WS, Gubala V, Nooney R, Williams DE, McDonagh C, et al. Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles. PLoS One 2012;7:e38129.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Köberle V, Kronenberger B, Pleli T, Trojan J, Imelmann E, Peveling-Oberhag J, et al. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer 2013;49:3442–3449.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qiang-Song Tong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mei, H., Lin, ZY. & Tong, QS. The roles of microRNAs in neuroblastoma. World J Pediatr 10, 10–16 (2014). https://doi.org/10.1007/s12519-014-0448-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-014-0448-2

Key words

Navigation