Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms

Journal of Hematology & Oncology

Emmanouel Kanavakis⁴  Fotini Tzortzatou-Stathopoulou⁵  Chara A Spiliopoulou²  Antonis Kattamis⁵  Aggeliki Kolialexi⁴  Neophytos Prodromou⁷  Diane K Birks¹  Kalliopi Stefanaki³  Vasilis Milionis⁵  Krinio Giannikou⁴  George I Lambrou⁵  Maria Braoudaki⁶ 

[1] Department of Neurosurgery, Anschutz Medical Campus, University of Colorado, Denver, CO, USA;Department of Forensic Medicine and Toxicology, School of Medicine, University of Athens, Athens, Greece;Department of Pathology, Children’s Hospital “Aghia Sophia”, Athens, Greece;Department of Medical Genetics, University of Athens, Athens, Greece;First Department of Pediatrics, University of Athens, Hematology and Oncology Unit, Choremeio Research Laboratory “Aghia Sophia” Children’s Hospital, Athens, Greece;First Department of Pediatrics, University of Athens Medical School, Choremeio Research Laboratory, Thivon & Levadias, 11527, Goudi, Athens, Greece;Department of Neurosurgery, Children’s Hospital “Aghia Sophia”, Athens, Greece

关键词: Biomarkers;    Prognosis;    MicroRNA microarrays;    Embryonal tumors;    Atypical teratoid/rhabdoid tumors;    Medulloblastomas;   

Others  :  1133475
DOI  :  10.1186/s13045-014-0096-y

 received in 2014-08-20, accepted in 2014-12-12,  发布年份 2014

【 摘 要 】

Background

Although, substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Recent microRNA (miRNA)-based research reveals the involvement of miRNAs in various aspects of CNS development and proposes that they might compose key molecules underlying oncogenesis. The current study evaluated miRNA differential expression detected between pediatric embryonal brain tumors and normal controls to characterize candidate biomarkers related to diagnosis, prognosis and therapy.

Methods

Overall, 19 embryonal brain tumors; 15 Medulloblastomas (MBs) and 4 Atypical Teratoid/Rabdoid Tumors (AT/RTs) were studied. As controls, 13 samples were used; The First-Choice Human Brain Reference RNA and 12 samples from deceased children who underwent autopsy and were not present with any brain malignancy. RNA extraction was carried out using the Trizol method, whilst miRNA extraction was performed with the mirVANA miRNA isolation kit. The experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative Real-Time Polymerase Chain Reaction was performed to validate the expression profiles of miR-34a and miR-601 in all 32 samples initially screened with miRNA microarrays and in an additional independent cohort of 30 patients (21MBs and 9 AT/RTs). Moreover, meta-analyses was performed in total 27 embryonal tumor samples; 19 MBs, 8 ATRTs and 121 control samples. Twelve germinomas were also used as an independent validation cohort. All deregulated miRNAs were correlated to patients’ clinical characteristics and pathological measures.

Results

In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics. Based on that, miR-601 could serve as a putative tumor suppressor gene, whilst miR-34a as an oncogene. In general, miR-34a demonstrated oncogenic roles in all pediatric embryonal CNS neoplasms studied.

Conclusions

Deeper understanding of the aberrant miRNA expression in pediatric embryonal brain tumors might aid in the development of tumor-specific miRNA signatures, which could potentially afford promising biomarkers related to diagnosis, prognosis and patient targeted therapy.

【 授权许可】

   
2014 Braoudaki et al.; licensee Biomed Central.

【 图 表 】

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【 参考文献 】

• [1]Fibriani A, Wisaksana R, Indrati A, Hartantri Y, van de Vijver D, Schutten M, Alisjahbana B, Sudjana P, Boucher CA, van Crevel R, van der Ven A: Virological failure and drug resistance during first line anti-retroviral treatment in Indonesia. J Med Virol 2013, 85:1394-1401.
• [2]Heath JA, Zacharoulis S, Kieran MW: Pediatric neuro-oncology: current status and future directions. Asia Pac J Clin Oncol 2012, 8:223-231.
• [3]Gokhale A, Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A, Mamidipally C, Noronha S, Kannan S, Shirsat NV: Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway. J Canc Res Ther 2010, 6:521-529.
• [4]Fernandez LA, Northcott PA, Taylor MD, Kenney AM: Normal and oncogenic roles for microRNAs in the developing brain. Cell Cycle 2009, 8:4049-4054.
• [5]Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, Giangaspero F, Ellison DW, Garre ML, Biassoni V, Grundy RG, Finlay JL, Dhall G, Raquin MA, Grill J: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 2010, 28:4961-4968.
• [6]Alitalo K, Schwab M: Oncogene amplification in tumor cells. Adv Cancer Res 1986, 47:235-281.
• [7]MacDonald TJ: Aggressive infantile embryonal tumors. J Child Neurol 2008, 23:1195-1204.
• [8]Guo H, Ingolia NT, Weissman JS, Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010, 466:835-840.
• [9]Lucon DR, Rocha Cde S, Craveiro RB, Dilloo D, Cardinalli IA, Cavalcanti DP, Aguiar Sdos S, Maurer-Morelli C, Yunes JA: Downregulation of 14q32 microRNAs in Primary Human Desmoplastic Medulloblastoma. Front Oncol 2013, 3:254.
• [10]Li KK, Pang JC, Ching AK, Wong CK, Kong X, Wang Y, Zhou L, Chen Z, Ng HK: miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol 2009, 40:1234-1243.
• [11]De Tullio G, De Fazio V, Sgherza N, Minoia C, Serrati S, Merchionne F, Loseto G, Iacobazzi A, Rana A, Petrillo P, Silvestris N, Iacopino P, Guarini A: Challenges and opportunities of microRNAs in lymphomas. Molecules 2014, 19:14723-14781.
• [12]Gayral M, Jo S, Hanoun N, Vignolle-Vidoni A, Lulka H, Delpu Y, Meulle A, Dufresne M, Humeau M, Chalret du Rieu M, Bournet B, Selves J, Guimbaud R, Carrere N, Buscail L, Torrisani J, Cordelier P: MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer. World J Gastroenterol 2014, 20:11199-11209.
• [13]Jeong HC: Clinical aspect of microRNA in lung cancer. Tuberc Respir Dis (Seoul) 2014, 77:60-64.
• [14]Nana-Sinkam SP, Croce CM: Clinical applications for microRNAs in cancer. Clin Pharmacol Ther 2013, 93:98-104.
• [15]Ren Y, Kang CS, Yuan XB, Zhou X, Xu P, Han L, Wang GX, Jia Z, Zhong Y, Yu S, Sheng J, Pu PY: Co-delivery of as-miR-21 and 5-FU by poly(amidoamine) dendrimer attenuates human glioma cell growth in vitro. J Biomater Sci Polym Ed 2010, 21:303-314.
• [16]Yang HW, Huang CY, Lin CW, Liu HL, Huang CW, Liao SS, Chen PY, Lu YJ, Wei KC, Ma CC: Gadolinium-functionalized nanographene oxide for combined drug and microRNA delivery and magnetic resonance imaging. Biomaterials 2014, 35:6534-6542.
• [17]Bader AG: miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 2012, 3:120.
• [18]Dalgard CL, Gonzalez M, deNiro JE, O’Brien JM: Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Invest Ophthalmol Vis Sci 2009, 50:4542-4551.
• [19]Li XJ, Ren ZJ, Tang JH: MicroRNA-34a: a potential therapeutic target in human cancer. Cell Death Dis 2014, 5:e1327.
• [20]Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R: MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009, 69:7569-7576.
• [21]Sun L, Wu Z, Shao Y, Pu Y, Miu W, Yao J, Wu Y, Yang Z: MicroRNA-34a suppresses cell proliferation and induces apoptosis in U87 glioma stem cells. Technol Canc Res Treat 2012, 11:483-490.
• [22]Wang X, Dong K, Gao P, Long M, Lin F, Weng Y, Ouyang Y, Ren J, Zhang H: microRNA-34a sensitizes lung cancer cell lines to DDP treatment independent of p53 status. Cancer Biother Radiopharm 2013, 28:45-50.
• [23]Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS, Di Rocco C, Riccardi R, Giangaspero F, Farcomeni A, Nofroni I, Laneve P, Gioia U, Caffarelli E, Bozzoni I, Screpanti I, Gulino A: MicroRNA profiling in human medulloblastoma. Int J Cancer 2009, 124:568-577.
• [24]Liu Y, Tang K, Yan W, Wang Y, You G, Kang C, Jiang T, Zhang W: Identifying Ki-67 specific miRNA-mRNA interactions in malignant astrocytomas. Neurosci Lett 2013, 546:36-41.
• [25]Guan Y, Mizoguchi M, Yoshimoto K, Hata N, Shono T, Suzuki SO, Araki Y, Kuga D, Nakamizo A, Amano T, Ma X, Hayashi K, Sasaki T: MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance. Clin Cancer Res 2010, 16:4289-4297.
• [26]Venkataraman S, Birks DK, Balakrishnan I, Alimova I, Harris PS, Patel PR, Handler MH, Dubuc A, Taylor MD, Foreman NK, Vibhakar R: MicroRNA 218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma. J Biol Chem 2013, 288:1918-1928.
• [27]Visani M, de Biase D, Marucci G, Cerasoli S, Nigrisoli E, Bacchi Reggiani ML, Albani F, Baruzzi A, Pession A: group Ps: Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III. Mol Oncol 2014, 8:417-430.
• [28]Birks DK, Barton VN, Donson AM, Handler MH, Vibhakar R, Foreman NK: Survey of MicroRNA expression in pediatric brain tumors. Pediatr Blood Cancer 2011, 56:211-216.
• [29]Ho CY, Bar E, Giannini C, Marchionni L, Karajannis MA, Zagzag D, Gutmann DH, Eberhart CG, Rodriguez FJ: MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2. Neuro Oncol 2013, 15:69-82.
• [30]Shalaby T, Fiaschetti G, Baumgartner M, Grotzer MA: MicroRNA signatures as biomarkers and therapeutic target for CNS embryonal tumors: the pros and the cons. Int J Mol Sci 2014, 15:21554-21586.
• [31]Rao P, Benito E, Fischer A: MicroRNAs as biomarkers for CNS disease. Front Mol Neurosci 2013, 6:39.
• [32]Sredni ST, Huang CC, Bonaldo Mde F, Tomita T: MicroRNA expression profiling for molecular classification of pediatric brain tumors. Pediatr Blood Cancer 2011, 57:183-184.
• [33]Wu MY, Fu J, Xiao X, Wu J, Wu RC: MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Lett 2014, 354:311-319.
• [34]Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, Zarone MR, Gulla A, Tagliaferri P, Tassone P, Caraglia M: Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids 2014, 3:e194.
• [35]Park EY, Chang E, Lee EJ, Lee HW, Kang HG, Chun KH, Woo YM, Kong HK, Ko JY, Suzuki H, Song E, Park JH: Targeting of miR34a-NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance.Cancer Res 2014, 74:7573–7582. doi:10.1158/0008-5472.CAN-14-1140.
• [36]Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, Cai W, Chirino LM, Yang GR, Bronson R, Crowley DG, Sahay G, Schroeder A, Langer R, Anderson DG, Jacks T: Small RNA combination therapy for lung cancer. Proc Natl Acad Sci U S A 2014, 111:E3553-3561.
• [37]De Antonellis P, Carotenuto M, Vandenbussche J, De Vita G, Ferrucci V, Medaglia C, Boffa I, Galiero A, Di Somma S, Magliulo D, Aiese N, Alonzi A, Spano D, Liguori L, Chiarolla C, Verrico A, Schulte JH, Mestdagh P, Vandesompele J, Gevaert K, Zollo M: Early targets of miR-34a in neuroblastoma. Mol Cell Proteomics 2014, 13:2114-2131.
• [38]Peng Y, Guo JJ, Liu YM, Wu XL: MicroRNA-34A inhibits the growth, invasion and metastasis of gastric cancer by targeting PDGFR and MET expression.Biosci Rep 2014, 34(3). doi: 10.1042/BSR20140020.
• [39]Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R: microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 2010, 9:1031-1036.
• [40]Rathod SS, Rani SB, Khan M, Muzumdar D, Shiras A: Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways. FEBS Open Biol 2014, 4:485-495.
• [41]Thor T, Kunkele A, Pajtler KW, Wefers AK, Stephan H, Mestdagh P, Heukamp L, Hartmann W, Vandesompele J, Sadowski N, Becker L, Garrett L, Holter SM, Horsch M, Calzada-Wack J, Klein-Rodewald T, Racz I, Zimmer A, Beckers J, Neff F, Klopstock T, Antonellis PD, Zollo M, Wurst W, Fuchs H, Gailus-Durner V, Schuller U, de Angelis MH, Eggert A, Schramm A, Schulte JH: MiR-34a deficiency accelerates medulloblastoma formation in vivo.Int J Cancer 2014. doi: 10.1002/ijc.29294. [Epub ahead of print].
• [42]Yin D, Ogawa S, Kawamata N, Leiter A, Ham M, Li D, Doan NB, Said JW, Black KL, Phillip Koeffler H: miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Oncogene 2013, 32:1155-1163.
• [43]Knight JR, Allison SJ, Milner J: Active regulator of SIRT1 is required for cancer cell survival but not for SIRT1 activity. Open Biol 2013, 3:130130.
• [44]Yamakuchi M, Ferlito M, Lowenstein CJ: miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A 2008, 105:13421-13426.
• [45]Yamakuchi M: MicroRNA regulation of SIRT1. Front Physiol 2012, 3:68.
• [46]Fan YN, Meley D, Pizer B, See V: Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells. PLoS One 2014, 9:e108514.
• [47]Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L, Zhang WG, Nan KJ, Song TS, Huang C: MicroRNA profiling of human gastric cancer. Mol Med Rep 2009, 2:963-970.
• [48]Costa FF, Bischof JM, Vanin EF, Lulla RR, Wang M, Sredni ST, Rajaram V, Bonaldo Mde F, Wang D, Goldman S, Tomita T, Soares MB: Identification of microRNAs as potential prognostic markers in ependymoma. PLoS One 2011, 6:e25114.
• [49]Ruiz Esparza-Garrido R, Velazquez-Flores MA, Diegoperez-Ramirez J, Lopez-Aguilar E, Siordia-Reyes G, Hernandez-Ortiz M, Martinez-Batallar AG, Encarnacion-Guevara S, Salamanca-Gomez F, Arenas-Aranda DJ: A proteomic approach of pediatric astrocytomas: MiRNAs and network insight. J Proteomics 2013, 94:162-175.
• [50]Zhao C, Zhang J, Zhang S, Yu D, Chen Y, Liu Q, Shi M, Ni C, Zhu M: Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma. Oncol Rep 2013, 30:276-284.
• [51]Chen Q, Ge X, Zhang Y, Xia H, Yuan D, Tang Q, Chen L, Pang X, Leng W, Bi F: Plasma miR-122 and miR-192 as potential novel biomarkers for the early detection of distant metastasis of gastric cancer. Oncol Rep 2014, 31:1863-1870.
• [52]Geng L, Chaudhuri A, Talmon G, Wisecarver JL, Are C, Brattain M, Wang J: MicroRNA-192 suppresses liver metastasis of colon cancer.Oncogene 2013.
• [53]Liu F, Xiong Y, Zhao Y, Tao L, Zhang Z, Zhang H, Liu Y, Feng G, Li B, He L, Ma J, Qin S, Yang Y: Identification of aberrant microRNA expression pattern in pediatric gliomas by microarray.Diagn Pathol 2013, 8:158. doi: 10.1186/1746-1596-8-158.
• [54]Miele E, Buttarelli FR, Arcella A, Begalli F, Garg N, Silvano M, Po A, Baldi C, Carissimo G, Antonelli M, Spinelli GP, Capalbo C, Donofrio V, Morra I, Nozza P, Gulino A, Giangaspero F, Ferretti E: High-throughput microRNA profiling of pediatric high-grade gliomas. Neuro Oncol 2014, 16:228-240.
• [55]Yang C, Wang C, Chen X, Chen S, Zhang Y, Zhi F, Wang J, Li L, Zhou X, Li N, Pan H, Zhang J, Zen K, Zhang CY, Zhang C: Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int J Cancer 2013, 132:116-127.
• [56]Packer RJ, Cohen BH, Cooney K: Intracranial germ cell tumors. Oncologist 2000, 5:312-320.
• [57]Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N, Berthold F, Henze G, Wolff JE, Warmuth-Metz M, Soerensen N, Emser A, Ottensmeier H, Deinlein F, Schlegel PG, Kortmann RD, Pietsch T, Kuehl J: German Pediatric Brain Tumor Study G: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 2009, 11:201-210.
• [58]Pinheiro I, Dejager L, Libert C: X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. Bioessays 2011, 33:791-802.
• [59]Wang Q, Huang Z, Ni S, Xiao X, Xu Q, Wang L, Huang D, Tan C, Sheng W, Du X: Plasma miR-601 and miR-760 are novel biomarkers for the early detection of colorectal cancer. PLoS One 2012, 7:e44398.
• [60]Lerebours F, Cizeron-Clairac G, Susini A, Vacher S, Mouret-Fourme E, Belichard C, Brain E, Alberini JL, Spyratos F, Lidereau R, Bieche I: miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness. Int J Cancer 2013, 133:1614-1623.
• [61]Li LZ, Zhang CZ, Liu LL, Yi C, Lu SX, Zhou X, Zhang ZJ, Peng YH, Yang YZ, Yun JP: miR-720 inhibits tumor invasion and migration in breast cancer by targeting TWIST1. Carcinogenesis 2014, 35:469-478.
• [62]Liu L, Chen K, Wu J, Shi L, Hu B, Cheng S, Li M, Song L: Downregulation of miR-452 promotes stem-like traits and tumorigenicity of gliomas. Clin Cancer Res 2013, 19:3429-3438.
• [63]Nassirpour R, Mehta PP, Yin MJ: miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting AKT3. PLoS One 2013, 8:e79655.
• [64]Nakao K, Miyaaki H, Ichikawa T: Antitumor function of microRNA-122 against hepatocellular carcinoma. J Gastroenterol 2014, 49:589-593.
• [65]Wang B, Wang H, Yang Z: MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One 2012, 7:e47053.
• [66]Wang G, Zhao Y, Zheng Y: miR-122/Wnt/beta-catenin regulatory circuitry sustains glioma progression.Tumour Biol 2014, 35(9):8565–8572. doi:10.1007/s13277-014-2089-4. Epub 2014 May 27.
• [67]Avalos Y, Canales J, Bravo-Sagua R, Criollo A, Lavandero S, Quest AF: Tumor suppression and promotion by autophagy. Biomed Res Int 2014, 2014:603980.
• [68]Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007, 114:97-109.
• [69]Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ, Hsu MT, Wong TT: Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. BMC Genomics 2010, 11:132. BioMed Central Full Text
• [70]Moreau MP, Bruse SE, Jornsten R, Liu Y, Brzustowicz LM: Chronological changes in microRNA expression in the developing human brain. PLoS One 2013, 8:e60480.
• [71]Sifakis EG, Lambrou GI, Prentza A, Vlahopoulos S, Koutsouris D, Tzortzatou-Stathopoulou F, Chatziioannou AA: Elucidating the identity of resistance mechanisms to prednisolone exposure in acute lymphoblastic leukemia cells through transcriptomic analysis: a computational approach. J Clin Bioinform 2011, 1:36. BioMed Central Full Text
• [72]Cardillo G: ROC curve: compute a Receiver Operating Characteristics curve. 2008
• [73]Zhang B, Kirov S, Snoddy J: WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 2005, 33:W741-W748.
• [74]Wang J, Duncan D, Shi Z, Zhang B: WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 2013, 41:W77-W83.