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miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas

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Tumor Biology


In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.

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Area under the curve


Central nervous system


Differentially expressed






Pilocytic astrocytomas


Quantitative real-time polymerase chain reaction


Receiver operating characteristic curves


World Health Organization


  1. Ha M, Kim VN. Regulation of microRNA biogenesis. Nature Rev Mol Cell Biol. 2014;15:509–24.

    Article  CAS  Google Scholar 

  2. Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Current genomics. 2010;11:537–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Braoudaki M, Lambrou GI. MicroRNAs in pediatric central nervous system embryonal neoplasms: the known unknown. J Hematol Oncol. 2015;8:6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Braoudaki M, Lambrou GI, Giannikou K, Milionis V, Stefanaki K, Birks DK, et al. MicroRNA expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms. J Hematol Oncol. 2014;7:96.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Arunachalam G, Upadhyay R, Ding H, Triggle CR. MicroRNA signature and cardiovascular dysfunction. J Cardiovascular Pharmacol. 2015;65:419–29.

    Article  CAS  Google Scholar 

  6. Mohammad AA, Rahbar A, Lui WO, Davoudi B, Catrina A, Stragliotto G, et al. Detection of circulating hcmv-miR-UL112-3p in patients with glioblastoma, rheumatoid arthritis, diabetes mellitus and healthy controls. PLoS One. 2014;9:e113740.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lycoudi A, Mavreli D, Mavrou A, Papantoniou N, Kolialexi A. MiRNAs in pregnancy-related complications. Expert Rev Mol Diagn. 2015;15:999–1010.

    Article  CAS  PubMed  Google Scholar 

  8. Birks DK, Barton VN, Donson AM, Handler MH, Vibhakar R, Foreman NK. Survey of microRNA expression in pediatric brain tumors. Pediatr Blood Cancer. 2011;56:211–6.

    Article  PubMed  Google Scholar 

  9. Braoudaki M, Lambrou GI, Papadodima SA, Stefanaki K, Prodromou N, Kanavakis E. MicroRNA expression profiles in pediatric dysembryoplastic neuroepithelial tumors. Medical Oncol (Northwood, London, England). 2016;33:5.

    Article  CAS  Google Scholar 

  10. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang B, Kirov S, Snoddy J. WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 2005;33:W741–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Agarwal V, Bell GW, Nam JW, Bartel DP: Predicting effective microRNA target sites in mammalian mRNAs. eLife 2015;4

  13. Paraskevopoulou MD, Georgakilas G, Kostoulas N, Reczko M, Maragkakis M, Dalamagas TM, et al. DIANA-LncBase: experimentally verified and computationally predicted microRNA targets on long non-coding RNAs. Nucleic Acids Res. 2013;41:D239–45.

    Article  CAS  PubMed  Google Scholar 

  14. Paraskevopoulou MD, Georgakilas G, Kostoulas N, Vlachos IS, Vergoulis T, Reczko M, et al. DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res. 2013;41:W169–73.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vlachos IS, Kostoulas N, Vergoulis T, Georgakilas G, Reczko M, Maragkakis M, et al. DIANA miRPath v. 2.0: investigating the combinatorial effect of microRNAs in pathways. Nucleic Acids Res. 2012;40:W498–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nishimura M, Jung EJ, Shah MY, Lu C, Spizzo R, Shimizu M, et al. Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov. 2013;3:1302–15.

    Article  CAS  PubMed  Google Scholar 

  17. Song G, Gu L, Li J, Tang Z, Liu H, Chen B, et al. Serum microRNA expression profiling predict response to r-chop treatment in diffuse large B cell lymphoma patients. Annals Hematol. 2014;93:1735–43.

    Article  CAS  Google Scholar 

  18. Huang E, Liu R, Chu Y. MiRNA-15a/16: as tumor suppressors and more. Future Oncol(London, England). 2015;11:2351–63.

    Article  CAS  Google Scholar 

  19. Kramer K, Wu J, Crowe DL: Tumor suppressor control of the cancer stem cell niche. Oncogene 2015

  20. Lan F, Yue X, Ren G, Li H, Ping L, Wang Y, et al. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway. Int J Radiat Oncol, Biol, physics. 2015;91:73–81.

    Article  CAS  Google Scholar 

  21. Lopez-Bertoni H, Lal B, Li A, Caplan M, Guerrero-Cazares H, Eberhart CG, et al. DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene. 2015;34:3994–4004.

    Article  CAS  PubMed  Google Scholar 

  22. Mishra PJ, Song B, Mishra PJ, Wang Y, Humeniuk R, Banerjee D, et al. MiR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism. PLoS One. 2009;4:e8445.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tian X, Zhang J, Yan L, Dong JM, Guo Q. MiRNA-15a inhibits proliferation, migration and invasion by targeting TNFAIP1 in human osteosarcoma cells. Int J Clin Exp Pathol. 2015;8:6442–9.

    PubMed  PubMed Central  Google Scholar 

  24. Tafsiri E, Darbouy M, Shadmehr MB, Zagryazhskaya A, Alizadeh J, Karimipoor M. Expression of miRNAs in non-small-cell lung carcinomas and their association with clinicopathological features. Tumour Biol. 2015;36:1603–12.

    Article  CAS  PubMed  Google Scholar 

  25. Yang T, Thakur A, Chen T, Yang L, Lei G, Liang Y, et al. MicroRNA-15a induces cell apoptosis and inhibits metastasis by targeting BCL2L2 in non-small cell lung cancer. Tumour Biol. 2015;36:4357–65.

    Article  CAS  PubMed  Google Scholar 

  26. Luo Q, Li X, Li J, Kong X, Zhang J, Chen L, et al. Mir-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer. Int J Oncol. 2013;43:1212–8.

    CAS  PubMed  Google Scholar 

  27. Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, et al. Targeting of YAP1 by MicroRNA-15a and MicroRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 2015;14:52.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Fallah P, Amirizadeh N, Poopak B, Toogeh G, Arefian E, Kohram F, et al. Expression pattern of key microRNAs in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Int J Lab Hematol. 2015;37:560–8.

    Article  CAS  PubMed  Google Scholar 

  29. Xiao G, Tang H, Wei W, Li J, Ji L, Ge J. Aberrant expression of microRNA-15a and microRNA-16 synergistically associates with tumor progression and prognosis in patients with colorectal cancer. Gastroenterology Res Pract. 2014;2014:364549.

    Google Scholar 

  30. de Groen FL, Timmer LM, Menezes RX, Diosdado B, Hooijberg E, Meijer GA, et al. Oncogenic role of miR-15a-3p in 13q amplicon-driven colorectal adenoma-to-carcinoma progression. PLoS One. 2015;10:e0132495.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wu XJ, Pu XM, Zhao ZF, Zhao YN, Kang XJ, Wu WD, et al. The expression profiles of microRNAs in Kaposi’s sarcoma. Tumour Biol. 2015;36:437–46.

    Article  CAS  PubMed  Google Scholar 

  32. Costa FF, Bischof JM, Vanin EF, Lulla RR, Wang M, Sredni ST, et al. Identification of microRNAs as potential prognostic markers in ependymoma. PLoS One. 2011;6:e25114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sand M, Skrygan M, Sand D, Georgas D, Gambichler T, Hahn SA, et al. Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi. Cell Tissue Res. 2013;351:85–98.

    Article  CAS  PubMed  Google Scholar 

  34. Inoguchi S, Seki N, Chiyomaru T, Ishihara T, Matsushita R, Mataki H, et al. Tumour-suppressive microRNA-24-1 inhibits cancer cell proliferation through targeting FOXM1 in bladder cancer. FEBS Lett. 2014;588:3170–9.

    Article  CAS  PubMed  Google Scholar 

  35. Luzi E, Marini F, Giusti F, Galli G, Cavalli L, Brandi ML. The negative feedback-loop between the oncomir Mir-24-1 and menin modulates the Men1 tumorigenesis by mimicking the “Knudson’s Second Hit”. PLoS One. 2012;7:e39767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luzi E, Marini F, Tognarini I, Galli G, Falchetti A, Brandi ML. The regulatory network menin-microRNA 26a as a possible target for RNA-based therapy of bone diseases. Nucleic Acid Therapeutics. 2012;22:103–8.

    CAS  PubMed  Google Scholar 

  37. Nymark P, Guled M, Borze I, Faisal A, Lahti L, Salmenkivi K, et al. Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos- and histology-related changes in lung cancer. Genes Chromosom Cancer. 2011;50:585–97.

    Article  CAS  PubMed  Google Scholar 

  38. Zhao Z, Qin L, Li S: miR-411 contributes the cell proliferation of lung cancer by targeting FOXo1. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine 2015

  39. Xia K, Zhang Y, Cao S, Wu Y, Guo W, Yuan W, et al. miR-411 regulated ITCH expression and promoted cell proliferation in human hepatocellular carcinoma cells. Biomed Pharmacother. 2015;70:158–63.

    Article  CAS  PubMed  Google Scholar 

  40. Nadal E, Zhong J, Lin J, Reddy RM, Ramnath N, Orringer MB, et al. A microRNA cluster at 14q32 drives aggressive lung adenocarcinoma. Clin Cancer Res. 2014;20:3107–17.

    Article  CAS  PubMed  Google Scholar 

  41. Skalsky RL, Cullen BR. Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One. 2011;6:e24248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marti E, Pantano L, Banez-Coronel M, Llorens F, Minones-Moyano E, Porta S, et al. A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucleic Acids Res. 2010;38:7219–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou AG, et al. Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. 2008;36:5270–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors’ contributions

MB conceived and designed the study, performed all experiments, evaluated and interpreted data analyses, and drafted the manuscript. GIL performed all data analyses and participated in interpretation of data analyses and in drafting the manuscript. GK assisted in microarrays performance. SAP performed resections of the postmortem specimens. AL performed qRT-PCR experiments. KS performed tumor diagnosis. GS performed all tumor resections. FTS treated patients. AK, FTS, MT, KTS, and EK participated in the coordination and supervision of the study. All authors approved the final manuscript.

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Correspondence to M. Braoudaki.

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The authors declare no competing financial or nonfinancial interests.

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Supplementary Table 1

miRNA functional annotation. Predictions of miRNA targets and pathway participation(XLSX 107 kb)

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Braoudaki, M., Lambrou, G.I., Giannikou, K. et al. miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas. Tumor Biol. 37, 9887–9897 (2016).

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