A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma

Megiorni,Francesca; Colaiacovo,Moreno; Cialfi,Samantha; McDowell,Heather P.; Guffanti,Alessandro; Camero,Simona; Felsani,Armando; Losty,Paul D.; Pizer,Barry; Shukla,Rajeev; Cappelli,Carlo; Ferrara,Eva; Pizzuti,Antonio; Moles,Anna; Dominici,Carlo

doi:10.3892/or.2017.5701

A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma

Authors:
- Francesca Megiorni
- Moreno Colaiacovo
- Samantha Cialfi
- Heather P. McDowell
- Alessandro Guffanti
- Simona Camero
- Armando Felsani
- Paul D. Losty
- Barry Pizer
- Rajeev Shukla
- Carlo Cappelli
- Eva Ferrara
- Antonio Pizzuti
- Anna Moles
- Carlo Dominici
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Affiliations: Department of Paediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, I-00161 Rome, Italy, Genomnia s.r.l., I-20091 Bresso, MI, Italy, Department of Molecular Medicine, Sapienza University of Rome, I-00161 Rome, Italy, Department of Paediatric Surgery, Alder Hey Children's NHS Foundation Trust, L12 2AP Liverpool, UK, Department of Oncology, Alder Hey Children's NHS Foundation Trust, L12 2AP Liverpool, UK, Department of Perinatal and Paediatric Pathology, Alder Hey Children's NHS Foundation Trust, L12 2AP Liverpool, UK, Department of Experimental Medicine, Sapienza University of Rome, I-00161 Rome, Italy
Published online on: June 6, 2017 https://doi.org/10.3892/or.2017.5701
Pages: 3-20
Copyright: © Megiorni et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN-amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control. Out of the 128 miRNAs differentially expressed in the NB vs. DRG comparison, 47 were expressed at higher levels, while 81 were expressed at lower levels in the NB tumours. We also found that 23 miRNAs were differentially expressed in NB with or without MYCN-amplification, with 17 miRNAs being upregulated and 6 being downregulated in the MNA subtypes. Functional annotation analysis of the target genes of these differentially expressed miRNAs demonstrated that many mRNAs were involved in cancer-related pathways, such as DNA-repair and apoptosis as well as FGFR and EGFR signalling. In particular, we found that miR-628-3p negatively affects MYCN gene expression. Furthermore, we identified a novel miRNA candidate with variable expression in MNA vs. MNnA tumours, whose putative target genes are implicated in the mTOR pathway. The present study provides further insight into the molecular mechanisms that correlate miRNA dysregulation to NB development and progression.

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1	Irwin MS and Park JR: Neuroblastoma: Paradigm for precision medicine. Pediatr Clin North Am. 62:225–256. 2015. View Article : Google Scholar : PubMed/NCBI
2	Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, et al: INRG Task Force: The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force report. J Clin Oncol. 27:289–297. 2009. View Article : Google Scholar : PubMed/NCBI
3	Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362:2202–2211. 2010. View Article : Google Scholar : PubMed/NCBI
4	Schwab M, Varmus HE, Bishop JM, Grzeschik KH, Naylor SL, Sakaguchi AY, Brodeur G and Trent J: Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature. 308:288–291. 1984. View Article : Google Scholar : PubMed/NCBI
5	Weiss WA, Aldape K, Mohapatra G, Feuerstein BG and Bishop JM: Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 16:2985–2995. 1997. View Article : Google Scholar : PubMed/NCBI
6	Yoshimoto M, De Toledo SR Caminada, Caran EM Monteiro, de Seixas MT, de Martino Lee ML, de Campos Vieira Abib S, Vianna SM, Schettini ST and Andrade J Anderson Duffles: MYCN gene amplification. Identification of cell populations containing double minutes and homogeneously staining regions in neuroblastoma tumors. Am J Pathol. 155:1439–1443. 1999. View Article : Google Scholar : PubMed/NCBI
7	Guglielmi L, Cinnella C, Nardella M, Maresca G, Valentini A, Mercanti D, Felsani A and DAgnano I: MYCN gene expression is required for the onset of the differentiation programme in neuroblastoma cells. Cell Death Dis. 5:e10812014. View Article : Google Scholar : PubMed/NCBI
8	Kaneko Y, Suenaga Y, Islam SM, Matsumoto D, Nakamura Y, Ohira M, Yokoi S and Nakagawara A: Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas. Cancer Sci. 106:840–847. 2015. View Article : Google Scholar : PubMed/NCBI
9	Lau DT, Flemming CL, Gherardi S, Perini G, Oberthuer A, Fischer M, Juraeva D, Brors B, Xue C, Norris MD, et al: MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma. Oncotarget. 6:15510–15523. 2015. View Article : Google Scholar : PubMed/NCBI
10	Beltran H: The N-myc Oncogene: Maximizing its targets, regulation, and therapeutic potential. Mol Cancer Res. 12:815–822. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zeng Y, Yi R and Cullen BR: MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA. 100:9779–9784. 2003. View Article : Google Scholar : PubMed/NCBI
12	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
13	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
14	Kozomara A and Griffiths-Jones S: miRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39(Database): D152–D157. 2011. View Article : Google Scholar : PubMed/NCBI
15	Friedman RC, Farh KK, Burge CB and Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19:92–105. 2009. View Article : Google Scholar : PubMed/NCBI
16	Domingo-Fernandez R, Watters K, Piskareva O, Stallings RL and Bray I: The role of genetic and epigenetic alterations in neuroblastoma disease pathogenesis. Pediatr Surg Int. 29:101–119. 2013. View Article : Google Scholar : PubMed/NCBI
17	Leichter AL, Sullivan MJ, Eccles MR and Chatterjee A: MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours. Mol Cancer. 16:152017. View Article : Google Scholar : PubMed/NCBI
18	Mei H, Lin ZY and Tong QS: The roles of microRNAs in neuroblastoma. World J Pediatr. 10:10–16. 2014. View Article : Google Scholar : PubMed/NCBI
19	Bray I, Tivnan A, Bryan K, Foley NH, Watters KM, Tracey L, Davidoff AM and Stallings RL: MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma. Cancer Lett. 303:56–64. 2011. View Article : Google Scholar : PubMed/NCBI
20	Tivnan A, Tracey L, Buckley PG, Alcock LC, Davidoff AM and Stallings RL: MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma. BMC Cancer. 11:332011. View Article : Google Scholar : PubMed/NCBI
21	Chen Y, Tsai YH, Fang Y and Tseng SH: Micro-RNA-21 regulates the sensitivity to cisplatin in human neuroblastoma cells. J Pediatr Surg. 47:1797–1805. 2012. View Article : Google Scholar : PubMed/NCBI
22	Ryan J, Tivnan A, Fay J, Bryan K, Meehan M, Creevey L, Lynch J, Bray IM, O'Meara A, Tracey L, et al: MicroRNA-204 increases sensitivity of neuroblastoma cells to cisplatin and is associated with a favourable clinical outcome. Br J Cancer. 107:967–976. 2012. View Article : Google Scholar : PubMed/NCBI
23	Teillet MA, Kalcheim C and Le Douarin NM: Formation of the dorsal root ganglia in the avian embryo: Segmental origin and migratory behavior of neural crest progenitor cells. Dev Biol. 120:329–347. 1987. View Article : Google Scholar : PubMed/NCBI
24	Beckwith JB and Martin RF: Observations on the histopathology of neuroblastomas. J Pediatr Surg. 3:106–110. 1968. View Article : Google Scholar : PubMed/NCBI
25	Griffiths-Jones S, Saini HK, van Dongen S and Enright AJ: miRBase: Tools for microRNA genomics. Nucleic Acids Res. 36(Database): D154–D158. 2008. View Article : Google Scholar : PubMed/NCBI
26	Robinson MD and Oshlack A: A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11:R252010. View Article : Google Scholar : PubMed/NCBI
27	Bullard JH, Purdom E, Hansen KD and Dudoit S: Evaluation of statistical methods for normalization and differential expression in mRNA-Seq experiments. BMC Bioinformatics. 11:942010. View Article : Google Scholar : PubMed/NCBI
28	Hsu SD, Tseng YT, Shrestha S, Lin YL, Khaleel A, Chou CH, Chu CF, Huang HY, Lin CM, Ho SY, et al: miRTarBase update 2014: An information resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 42(D1): D78–D85. 2014. View Article : Google Scholar : PubMed/NCBI
29	Enright AJ, John B, Gaul U, Tuschl T, Sander C and Marks DS: MicroRNA targets in Drosophila. Genome Biol. 5:R12003. View Article : Google Scholar : PubMed/NCBI
30	Huang W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
31	Wu G, Feng X and Stein L: A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 11:R532010. View Article : Google Scholar : PubMed/NCBI
32	Wang J, Huang Q, Liu ZP, Wang Y, Wu LY, Chen L and Zhang XS: NOA: A novel network ontology analysis method. Nucleic Acids Res. 39:e872011. View Article : Google Scholar : PubMed/NCBI
33	Grant CE, Bailey TL and Noble WS: FIMO: Scanning for occurrences of a given motif. Bioinformatics. 27:1017–1018. 2011. View Article : Google Scholar : PubMed/NCBI
34	Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G and Durbin R: 1000 Genome Project Data Processing Subgroup: The Sequence Alignment/Map format and SAMtools. Bioinformatics. 25:2078–2079. 2009. View Article : Google Scholar : PubMed/NCBI
35	Friedländer MR, Chen W, Adamidi C, Maaskola J, Einspanier R, Knespel S and Rajewsky N: Discovering microRNAs from deep sequencing data using miRDeep. Nat Biotechnol. 26:407–415. 2008. View Article : Google Scholar : PubMed/NCBI
36	Megiorni F, Camero S, Ceccarelli S, McDowell HP, Mannarino O, Marampon F, Pizer B, Shukla R, Pizzuti A, Marchese C, et al: DNMT3B in vitro knocking-down is able to reverse embryonal rhabdomyosarcoma cell phenotype through inhibition of proliferation and induction of myogenic differentiation. Oncotarget. 7:79342–79356. 2016.PubMed/NCBI
37	Afanasyeva EA, Hotz-Wagenblatt A, Glatting KH and Westermann F: New miRNAs cloned from neuroblastoma. BMC Genomics. 9:522008. View Article : Google Scholar : PubMed/NCBI
38	Mestdagh P, Fredlund E, Pattyn F, Schulte JH, Muth D, Vermeulen J, Kumps C, Schlierf S, De Preter K, Van Roy N, et al: MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene. 29:1394–1404. 2010. View Article : Google Scholar : PubMed/NCBI
39	Bienertova-Vasku J, Mazanek P, Hezova R, Curdova A, Nekvindova J, Kren L, Sterba J and Slaby O: Extension of microRNA expression pattern associated with high-risk neuroblastoma. Tumour Biol. 34:2315–2319. 2013. View Article : Google Scholar : PubMed/NCBI
40	Uppal A, Wightman SC, Mallon S, Oshima G, Pitroda SP, Zhang Q, Huang X, Darga TE, Huang L, Andrade J, et al: 14q32-encoded microRNAs mediate an oligometastatic phenotype. Oncotarget. 6:3540–3552. 2015. View Article : Google Scholar : PubMed/NCBI
41	Liu L, Chen R, Zhang Y, Fan W, Xiao F and Yan X: Low expression of circulating microRNA-328 is associated with poor prognosis in patients with acute myeloid leukemia. Diagn Pathol. 10:1092015. View Article : Google Scholar : PubMed/NCBI
42	Yuan J, Zheng Z, Zheng Y, Lu X, Xu L and Lin L: microRNA-328 is a favorable prognostic marker in human glioma via suppressing invasive and proliferative phenotypes of malignant cells. Int J Neurosci. 126:145–153. 2015. View Article : Google Scholar : PubMed/NCBI
43	Anwar SL, Albat C, Krech T, Hasemeier B, Schipper E, Schweitzer N, Vogel A, Kreipe H and Lehmann U: Concordant hypermethylation of intergenic microRNA genes in human hepatocellular carcinoma as new diagnostic and prognostic marker. Int J Cancer. 133:660–670. 2013. View Article : Google Scholar : PubMed/NCBI
44	Shi S, Lu Y, Qin Y, Li W, Cheng H, Xu Y, Xu J, Long J, Liu L, Liu C, et al: miR-1247 is correlated with prognosis of pancreatic cancer and inhibits cell proliferation by targeting neuropilins. Curr Mol Med. 14:316–327. 2014. View Article : Google Scholar : PubMed/NCBI
45	Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, OBrien S, Kantarjian HM, et al: Targeting neuropilin-1 in human leukemia and lymphoma. Blood. 117:920–927. 2011. View Article : Google Scholar : PubMed/NCBI
46	Yan H, Choi AJ, Lee BH and Ting AH: Identification and functional analysis of epigenetically silenced microRNAs in colorectal cancer cells. PLoS One. 6:e206282011. View Article : Google Scholar : PubMed/NCBI
47	Charlet J, Schnekenburger M, Brown KW and Diederich M: DNA demethylation increases sensitivity of neuroblastoma cells to chemotherapeutic drugs. Biochem Pharmacol. 83:858–865. 2012. View Article : Google Scholar : PubMed/NCBI
48	Mestdagh P, Boström AK, Impens F, Fredlund E, Van Peer G, De Antonellis P, von Stedingk K, Ghesquière B, Schulte S, Dews M, et al: The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma. Mol Cell. 40:762–773. 2010. View Article : Google Scholar : PubMed/NCBI
49	Miao T, Wu D, Zhang Y, Bo X, Xiao F, Zhang X, Magoulas C, Subang MC, Wang P and Richardson PM: SOCS3 suppresses AP-1 transcriptional activity in neuroblastoma cells through inhibition of c-Jun N-terminal kinase. Mol Cell Neurosci. 37:367–375. 2008. View Article : Google Scholar : PubMed/NCBI
50	Morgan K, Stewart AJ, Miller N, Mullen P, Muir M, Dodds M, Medda F, Harrison D, Langdon S and Millar RP: Gonadotropin-releasing hormone receptor levels and cell context affect tumor cell responses to agonist in vitro and in vivo. Cancer Res. 68:6331–6340. 2008. View Article : Google Scholar : PubMed/NCBI
51	Weng WC, Lin KH, Wu PY, Lu YC, Weng YC, Wang BJ, Liao YF, Hsu WM, Lee WT and Lee H: Calreticulin regulates VEGF-A in neuroblastoma cells. Mol Neurobiol. 52:758–770. 2015. View Article : Google Scholar : PubMed/NCBI
52	Lodrini M, Oehme I, Schroeder C, Milde T, Schier MC, Kopp-Schneider A, Schulte JH, Fischer M, De Preter K, Pattyn F, et al: MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma. Nucleic Acids Res. 41:6018–6033. 2013. View Article : Google Scholar : PubMed/NCBI
53	Rihani A, Van Goethem A, Ongenaert M, De Brouwer S, Volders PJ, Agarwal S, De Preter K, Mestdagh P, Shohet J, Speleman F, et al: Genome wide expression profiling of p53 regulated miRNAs in neuroblastoma. Sci Rep. 5:90272015. View Article : Google Scholar : PubMed/NCBI
54	Murphy DM, Buckley PG, Bryan K, Das S, Alcock L, Foley NH, Prenter S, Bray I, Watters KM, Higgins D, et al: Global MYCN transcription factor binding analysis in neuroblastoma reveals association with distinct E-box motifs and regions of DNA hypermethylation. PLoS One. 4:e81542009. View Article : Google Scholar : PubMed/NCBI
55	Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers UC, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, et al: MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int J Cancer. 122:699–704. 2008. View Article : Google Scholar : PubMed/NCBI
56	Lovén J, Zinin N, Wahlström T, Müller I, Brodin P, Fredlund E, Ribacke U, Pivarcsi A, Påhlman S and Henriksson M: MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma. Proc Natl Acad Sci USA. 107:1553–1558. 2010. View Article : Google Scholar : PubMed/NCBI
57	He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, et al: A microRNA polycistron as a potential human oncogene. Nature. 435:828–833. 2005. View Article : Google Scholar : PubMed/NCBI
58	Mogilyansky E and Rigoutsos I: The miR-17/92 cluster: A comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 20:1603–1614. 2013. View Article : Google Scholar : PubMed/NCBI
59	Thorsen SB, Obad S, Jensen NF, Stenvang J and Kauppinen S: The therapeutic potential of microRNAs in cancer. Cancer J. 18:275–284. 2012. View Article : Google Scholar : PubMed/NCBI
60	Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M, Boldrini R, Donfrancesco A, Federici V, Giacomini P, et al: Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One. 3:e22362008. View Article : Google Scholar : PubMed/NCBI
61	Guo J, Dong Q, Fang Z, Chen X, Lu H, Wang K, Yin Y, Cai X, Zhao N, Chen J, et al: Identification of miRNAs that are associated with tumor metastasis in neuroblastoma. Cancer Biol Ther. 9:446–452. 2010. View Article : Google Scholar : PubMed/NCBI
62	Schulte JH, Marschall T, Martin M, Rosenstiel P, Mestdagh P, Schlierf S, Thor T, Vandesompele J, Eggert A, Schreiber S, et al: Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res. 38:5919–5928. 2010. View Article : Google Scholar : PubMed/NCBI
63	Rahmann S, Martin M, Schulte JH, Köster J, Marschall T and Schramm A: Identifying transcriptional miRNA biomarkers by integrating high-throughput sequencing and real-time PCR data. Methods. 59:154–163. 2013. View Article : Google Scholar : PubMed/NCBI
64	Chang YY, Kuo WH, Hung JH, Lee CY, Lee YH, Chang YC, Lin WC, Shen CY, Huang CS, Hsieh FJ, et al: Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer. 14:362015. View Article : Google Scholar : PubMed/NCBI
65	Zhang Y, Hu Y, Fang JY and Xu J: Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome. Oncotarget. 7:11056–11066. 2016.PubMed/NCBI
66	Pehserl AM, Ress AL, Stanzer S, Resel M, Karbiener M, Stadelmeyer E, Stiegelbauer V, Gerger A, Mayr C, Scheideler M, et al: Comprehensive analysis of miRNome alterations in response to sorafenib treatment in colorectal cancer cells. Int J Mol Sci. 17:E20112016. View Article : Google Scholar : PubMed/NCBI
67	Wang H, Zhi H, Ma D and Li T: MiR-217 promoted the proliferation and invasion of glioblastoma by repressing YWHAG. Cytokine. 92:93–102. 2017. View Article : Google Scholar : PubMed/NCBI
68	Kos A, Loohuis NF Olde, Wieczorek ML, Glennon JC, Martens GJ, Kolk SM and Aschrafi A: A potential regulatory role for intronic microRNA-338-3p for its host gene encoding apoptosis-associated tyrosine kinase. PLoS One. 7:e310222012. View Article : Google Scholar : PubMed/NCBI
69	Chen X, Pan M, Han L, Lu H, Hao X and Dong Q: miR-338-3p suppresses neuroblastoma proliferation, invasion and migration through targeting PREX2a. FEBS Lett. 587:3729–3737. 2013. View Article : Google Scholar : PubMed/NCBI
70	Chiang HR, Schoenfeld LW, Ruby JG, Auyeung VC, Spies N, Baek D, Johnston WK, Russ C, Luo S, Babiarz JE, et al: Mammalian microRNAs: Experimental evaluation of novel and previously annotated genes. Genes Dev. 24:992–1009. 2010. View Article : Google Scholar : PubMed/NCBI
71	Müller S and Nowak K: Exploring the miRNA-mRNA regulatory network in clear cell renal cell carcinomas by next-generation sequencing expression profiles. BioMed Res Int. 2014:9484082014. View Article : Google Scholar : PubMed/NCBI
72	Murphy DM, Buckley PG, Das S, Watters KM, Bryan K and Stallings RL: Co-localization of the oncogenic transcription factor MYCN and the DNA methyl binding protein MeCP2 at genomic sites in neuroblastoma. PLoS One. 6:e214362011. View Article : Google Scholar : PubMed/NCBI
73	Corvetta D, Chayka O, Gherardi S, DAcunto CW, Cantilena S, Valli E, Piotrowska I, Perini G and Sala A: Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: Functional and therapeutic implications. J Biol Chem. 288:8332–8341. 2013. View Article : Google Scholar : PubMed/NCBI
74	Buechner J and Einvik C: N-myc and noncoding RNAs in neuroblastoma. Mol Cancer Res. 10:1243–1253. 2012. View Article : Google Scholar : PubMed/NCBI
75	Jackstadt R and Hermeking H: MicroRNAs as regulators and mediators of c-MYC function. Biochim Biophys Acta. 1849:544–553. 2015. View Article : Google Scholar : PubMed/NCBI
76	Guo L and Chen F: A challenge for miRNA: Multiple isomiRs in miRNAomics. Gene. 544:1–7. 2014. View Article : Google Scholar : PubMed/NCBI
77	Iżycka-Świeszewska E, Drożyńska E, Rzepko R, Kobierska-Gulida G, Grajkowska W, Perek D and Balcerska A: Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours. Pol J Pathol. 61:192–198. 2010.PubMed/NCBI
78	King D, Yeomanson D and Bryant HE: PI3King the lock: Targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol. 37:245–251. 2015. View Article : Google Scholar : PubMed/NCBI
79	Vaughan L, Clarke PA, Barker K, Chanthery Y, Gustafson CW, Tucker E, Renshaw J, Raynaud F, Li X, Burke R, et al: Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. Oncotarget. 7:57525–57544. 2016.PubMed/NCBI