miRNA Manipulation in Modifying Radiation Sensitivity in Glioblastoma Models

  • Silvia Palumbo
  • G. Belmonte
  • Paolo Tini
  • Marzia Toscano
  • Clelia Miracco
  • Sergio CominciniEmail author
Part of the Current Clinical Pathology book series (CCPATH)


MicroRNA (miRNA) modulate the expression of virtually all genes of a cell and therefore are critical actors within the malignant transformation. miRNA are also endogenous molecular weapons of the tumor cells to respond to therapy: in human glioblastoma multiforme (GBM) cells miRNA can counteract the radiation effects interfering with signal transduction cascaded or controlling the fate of the cell by the regulation of programmed cell death processes. On the other hand, the modulation of specific GBM miRNA that contribute to the radio-resistance phenotype might represent a powerful molecular approach to favorably interfere within the altered gene network of human brain tumors.

In this review, we highlight the state of the art of the capacity of miRNA to modulate the behavior of glioblastoma cells to ionizing radiation preclinical schemes.


Gene expression Astrocytoma Glioma Radiotherapy RNA interference GBM cell lines 


  1. 1.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006;13: 1238–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T. Identification of a cancer stem cell in human brain tumors. Nature. 2004;432:396–401.PubMedCrossRefGoogle Scholar
  5. 5.
    Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: state of the art and future therapeutics. Surg Neurol Int. 2014;5:64.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Nakada M, Kita D, Watanabe T, Hayashi Y, Teng L, Pyko IV, et al. Aberrant signaling pathways in glioma. Cancers. 2011;3:3242–78.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Palumbo S, Miracco C, Pirtoli L, Comincini S. Emerging roles of microRNA in modulating cell-death processes in malignant glioma. J Cell Physiol. 2014;229:277–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol. 2014;16:4–9.CrossRefGoogle Scholar
  9. 9.
    Lee JK, Joo KM, Lee J, Yoon Y, Nam DH. Targeting the epithelial to mesenchymal transition in glioblastoma: the emerging role of MET signaling. Onco Targets Ther. 2014;7:1933–44.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34:732–40.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheng JX, Liu BL, Zhang X. How powerful is CD133 as a cancer stem cell marker in brain tumours? Cancer Treat Rev. 2009;35:403–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Oka N, Soeda A, Noda S, Iwama T. Brain tumor stem cells from an adenoid glioblastoma multiforme. Neurol Med Chir. 2009;49:146–51.CrossRefGoogle Scholar
  14. 14.
    Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, et al. CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol. 2008;18:370–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67–77.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    He J, Shan Z, Li L, Liu F, Liu Z, Song M, et al. Expression of glioma stem cell marker CD133 and O6-methylguanine-DNA methyltransferase is associated with resistance to radiotherapy in gliomas. Oncol Rep. 2011;26:1305–13.PubMedGoogle Scholar
  17. 17.
    Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66:7843–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Ropolo M, Daga A, Griffero F, Foresta M, Casartelli G, Zunino A, et al. Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Mol Cancer Res. 2009;7:383–92.PubMedCrossRefGoogle Scholar
  19. 19.
    McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ. CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res. 2009;15:5145–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Koshkin PA, Chistiakov DA, Chekhonin VP. Role of microRNAs in mechanisms of glioblastoma resistance to radio- and chemotherapy. Biochemistry. 2013;78:325–34.PubMedGoogle Scholar
  21. 21.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim VN. 2005. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6:376–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004;432:231–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123: 631–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Visone R, Croce CM. 2009. MiRNAs and cancer. Am J Pathol. 2009;174:1131–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10: 704–14.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Soifer HS, Rossi JJ, Saetrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther. 2007;15:2070–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Iorio MV, Croce CM. MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol. 2009;27:5848–56.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Lee YS, Dutta A. MicroRNAs: small but potent oncogenes or tumor suppressors. Curr Opin Investig Drugs. 2006;7:560–4.PubMedGoogle Scholar
  31. 31.
    Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Kreth S, Thon N, Kreth FW. Epigenetics in human gliomas. Cancer Lett. 2014;342:185–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Calin GA, Croce CM. MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene. 2006;25:6202–10.PubMedCrossRefGoogle Scholar
  34. 34.
    Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007;67:2456–68.PubMedCrossRefGoogle Scholar
  36. 36.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, et al. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008;68:9125–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci U S A. 2010;107:2183–8.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS, et al. MicroRNA profiling in human medulloblastoma. Int J Cancer. 2009;124:568–77.PubMedCrossRefGoogle Scholar
  39. 39.
    Pang JC, Kwok WK, Chen Z, Ng HK. Oncogenic role of microRNAs in brain tumors. Acta Neuropathol. 2009;117:599–611.PubMedCrossRefGoogle Scholar
  40. 40.
    Rao SA, Santosh V, Somasundaram K. Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol. 2010;23:1404–17.PubMedCrossRefGoogle Scholar
  41. 41.
    Turner JD, Williamson R, Almefty KK, Nakaji P, Porter R, Tse V, et al. The many roles of microRNAs in brain tumor biology. Neurosurg Focus. 2010;28, E3.PubMedCrossRefGoogle Scholar
  42. 42.
    Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69:7569–76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Mei J, Bachoo R, Zhang CL. MicroRNA-146a inhibits glioma development by targeting Notch1. Mol Cell Biol. 2011;31:3584–92.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 2008;68:3566–72.PubMedCrossRefGoogle Scholar
  45. 45.
    Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas JC, Gill RM, Huillard E, et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene. 2008;31: 1884–95.CrossRefGoogle Scholar
  46. 46.
    Zhang QQ, Xu H, Huang MB, Ma LM, Huang QJ, Yao Q, et al. MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. Neuro Oncol. 2012;14: 278–87.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Al-Nedawi K, Meehan B, Rak J. Microvesicles: messengers and mediators of tumor progression. Cell Cycle. 2009;8:2014–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Antonyak MA, Li B, Boroughs LK, Johnson JL, Druso JE, Bryant KL, et al. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc Natl Acad Sci U S A. 2011;108:4852–7.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, et al. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009;23:1541–57.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470–6.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Godlewski J, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A. Belonging to a network-microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Neuro Oncol. 2015;17(5):652–62.PubMedCrossRefGoogle Scholar
  52. 52.
    Gagliano N, Costa F, Cossetti C, Pettinari L, Bassi R, Chiriva-Internati M, et al. Glioma–astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model. Oncol Rep. 2009;22:1349–56.PubMedCrossRefGoogle Scholar
  53. 53.
    Katakowski M, Buller B, Wang X, Rogers T, Chopp M. Functional microRNA is transferred between glioma cells. Cancer Res. 2010;70:8259–63.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Valiunas V, Polosina YY, Miller H, Potapova IA, Valiuniene L, Doronin S, et al. Connexin-specific cell to-cell transfer of short interfering RNA by gap junctions. J Physiol. 2005;568:459–68.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Chistiakov DA, Chekhonin VP. Contribution of microRNAs to radio- and chemoresistance of brain tumors and their therapeutic potential. Eur J Pharmacol. 2012;684:8–18.PubMedCrossRefGoogle Scholar
  56. 56.
    Broderick JA, Zamore PD. MicroRNA therapeutics. Gene Ther. 2011;18:1104–10.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kurreck J, Wyszko E, Gillen C, Erdmann VA. Design of antisense oligonucleotides stabilized by locked nucleic acids. Nucleic Acids Res. 2002;30:1911–8.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Stenvang J, Kauppinen S. MicroRNAs as targets for antisense-based therapeutics. Expert Opin Biol Ther. 2008;8:59–81.PubMedCrossRefGoogle Scholar
  59. 59.
    Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2009;327:198–201.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2: 751–60.PubMedCrossRefGoogle Scholar
  61. 61.
    Heurtault B, Saulnier P, Pech B, Proust JE, Benoit JP. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm Res. 2002;19:875–80.PubMedCrossRefGoogle Scholar
  62. 62.
    Allard E, Passirani C, Garcion E, Pigeon P, Vessières A, Jaouen G, et al. Lipid nanocapsules loaded with an organometallic tamoxifen derivative as a novel drug-carrier system for experimental malignant gliomas. J Control Release. 2008;130:146–53.PubMedCrossRefGoogle Scholar
  63. 63.
    Garcion E, Lamprecht A, Heurtault B, Paillard A, Aubert-Pouessel A, Denizot B, et al. A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats. Mol Cancer Ther. 2006;5:1710–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Lacoeuille F, Garcion E, Benoit JP, Lamprecht A. Lipid nanocapsules for intracellular drug delivery of anticancer drugs. J Nanosci Nanotechnol. 2007;7:4612–7.PubMedGoogle Scholar
  65. 65.
    Paillard A, Hindré F, Vignes-Colombeix C, Benoit JP, Garcion E. The importance of endo-lysosomal escape with lipid nanocapsules for drug subcellular bioavailability. Biomaterials. 2010;31:7542–54.PubMedCrossRefGoogle Scholar
  66. 66.
    Roger E, Lagarce F, Garcion E, Benoit JP. Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. J Control Release. 2009;140:174–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Weyland M, Manero F, Paillard A, Grée D, Viault G, Jarnet D, et al. Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1. J Control Release. 2011;151:74–82.PubMedCrossRefGoogle Scholar
  68. 68.
    Ballot S, Noiret N, Hindré F, Denizot B, Garin E, Rajerison H, et al. 99mTc/188Re-labelled lipid nanocapsules as promising radiotracers for imaging and therapy: formulation and biodistribution. Eur J Nucl Med Mol Imaging. 2006;33:602–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Vanpouille-Box C, Lacoeuille F, Roux J, Aubé C, Garcion E, Lepareur N, et al. Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model. PLoS One. 2011;6, e16926.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Griveau I, Bejaud J, Anthiya S, Avril S, Autret D, Garcion E. Silencing of miR-21 by locked nucleic acid-lipid nanocapsule complexes sensitize human glioblastoma cells to radiation-induced cell death. Int J Pharm. 2013;454:765–74.PubMedCrossRefGoogle Scholar
  71. 71.
    Palumbo S, Comincini S. Autophagy and ionizing radiation in tumors: the “survive or not survive” dilemma. J Cell Physiol. 2013;228:1–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Yu KN, Han W. Ionizing radiation, DNA double strand break, and mutation. In: Urbano KV, editor. Advances in genetics research, vol. 4. New York: Nova Science; 2010.Google Scholar
  73. 73.
    Lee KM, Choi EJ, Kim IA. microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother Oncol. 2011;101:171–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC. Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell. 2010;18:619–29.PubMedCrossRefGoogle Scholar
  75. 75.
    Besse A, Sana J, Fadrus P, Slaby O. MicroRNAs involved in chemo- and radioresistance of high-grade gliomas. Tumour Biol. 2013;34:1969–78.PubMedCrossRefGoogle Scholar
  76. 76.
    Guillamo JS, de Boüard S, Valable S, Marteau L, Leuraud P, Marie Y. Molecular mechanisms underlying effects of epidermal growth factor receptor inhibition on invasion, proliferation, and angiogenesis in experimental glioma. Clin Cancer Res. 2009;15:3697–704.PubMedCrossRefGoogle Scholar
  77. 77.
    Chen G, Zhu W, Shi D, Lv L, Zhang C, Liu P. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep. 2010;23:997–1003.PubMedGoogle Scholar
  78. 78.
    Hara T, Omura-Minamisawa M, Kang Y, Cheng C, Inoue T. Flavopiridol potentiates the cytotoxic effects of radiation in radioresistant tumor cells in which p53 is mutated or Bcl-2 is overexpressed. Int J Radiat Oncol Biol Phys. 2008;71:1485–95.PubMedCrossRefGoogle Scholar
  79. 79.
    Krichevsky AM, Gabriely G. miR-21: a small multi-faceted RNA. J Cell Mol Med. 2009;13:39–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–33.PubMedCrossRefGoogle Scholar
  81. 81.
    Li Y, Zhao S, Zhen Y, Li Q, Teng L, Asai A, Kawamoto K. A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol. 2011;28:209–14.PubMedCrossRefGoogle Scholar
  82. 82.
    Chao TF, Xiong HH, Liu W, Chen Y, Zhang JX. MiR-21 mediates the radiation resistance of glioblastoma cells by regulating PDCD4 and hMSH2. J Huazhong Univ Sci Technolog Med Sci. 2013;33:525–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Zhou X, Ren Y, Moore L, Mei M, You Y, Mei P. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest. 2010;90:144–55.PubMedCrossRefGoogle Scholar
  84. 84.
    Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009;23:1327–37.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J. Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol Med. 2010;39:793–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Lindberg D, Hessman O, Akerstrom G, Westin G. Cyclin dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors. Neuroendocrinology. 2007;86:112–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Dobashi Y, Goto A, Fukayama M, Abe A, Ooi A. Overexpression of cdk4/cyclin D1, a possible mediator of apoptosis and an indicator of prognosis in human primary lung carcinoma. Int J Cancer. 2004;110:532–41.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang L, Yamane T, Satoh E, Amagasaki K, Kawataki T, Asahara T, et al. Establishment and partial characterization of five malignant glioma cell lines. Neuropathology. 2005;25:136–43.PubMedCrossRefGoogle Scholar
  89. 89.
    Shimura T, Noma N, Oikawa T, Ochiai Y, Kakuda S. Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells. Oncogenesis. 2012;1:e12.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Deng X, Ma L, Wu M, Zhang G, Jin C, Guo Y, et al. miR-124 radiosensitizes human glioma cells by targeting CDK4. J Neurooncol. 2013;114:263–74.PubMedCrossRefGoogle Scholar
  91. 91.
    Ng WL, Yan D, Zhang X, Mo YY, Wang Y. Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair. 2010;9:1170–5.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Chaudhry MA, Sachdeva H, Omaruddin RA. Radiation-induced micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways. DNA Cell Biol. 2010;29:553–61.PubMedCrossRefGoogle Scholar
  93. 93.
    Lin Y-X, Yu F, Gao N, Sheng J-P, Qiu J-Z, Hu B-C. microRNA-143 protects cells from DNA damage-induced killing by downregulating FHIT expression. Cancer Biother Radiopharm. 2011;26:365–72.PubMedCrossRefGoogle Scholar
  94. 94.
    Babar IA, Czochor J, Steinmetz A, Weidhaas JB, Glazer PM, Slack FJ. Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells. Cancer Biol Ther. 2011;12:908–14.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Poltronieri PI, D’Urso PI, Mezzolla V, D’Urso OF. Potential of anti-cancer therapy based on anti-miR-155 oligonucleotides in glioma and brain tumours. Chem Biol Drug Des. 2013;81:79–84.PubMedCrossRefGoogle Scholar
  96. 96.
    Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo Y-Y. Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One. 2010;5, e11397.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Mueller AC, Sun D, Dutta A. The miR-99 family regulates the DNA damage response through its target SNF2H. Oncogene. 2012;32:1164–72.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Mirzayans R, Andrais B, Scott A, Murray D. New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J Biomed Biotechnol. 2012;2012:170325. doi: 10.1155/2012/170325.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Le MTN, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V. MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 2009;23:862–76.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Luan S, Sun L, Huang F. MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U251. Arch Med Res. 2010;41:67–74.PubMedCrossRefGoogle Scholar
  101. 101.
    Sasaki A, Udaka Y, Tsunoda Y, Yamamoto G, Tsuji M, Oyamada H. Analysis of p53 and miRNA expression after irradiation of glioblastoma cell lines. Anticancer Res. 2012;32:4709–13.PubMedGoogle Scholar
  102. 102.
    Niemoeller OM, Niyazi M, Corradini S, Zehentmayr F, Li M, Lauber K, et al. MicroRNA expression profiles in human cancer cells after ionizing radiation. Radiat Oncol. 2011;6:29–37.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Ding J, Huang S, Wu S, Zhao Y, Liang L, Yan M, Ge C, et al. Gain of miR-151 on chromosome 8q24.3 facilitates tumor cell migration and spreading through downregulating RhoGDIA. Nat. Cell Biol. 2010;12:390–9.Google Scholar
  104. 104.
    Qin W, Shi Y, Zhao B, Yao C, Jin L, Ma J, et al. miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells. PLoS One. 2010;5:e9429.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Tian S, Huang S, Wu S, Guo W, Li J, He X. MicroRNA-1285 inhibits the expression of p53 by directly targeting its 3′ untranslated region. Biochem Biophys Res Commun. 2010;396:435–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res. 2001;61:2744–50.PubMedGoogle Scholar
  107. 107.
    Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, et al. Let-7 microRNA inhibits the proliferation of human glioblastoma cells. DNA Cell Biol. 2010;29:553–61.CrossRefGoogle Scholar
  108. 108.
    Li W, Guo F, Wang P, Hong S, Zhang C. miR-221/222 confers radioresistance in glioblastoma cells through activating Akt independent of PTEN status. Curr Mol Med. 2014;14:185–95.PubMedCrossRefGoogle Scholar
  109. 109.
    Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, et al. hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res. 2008;1236:185–93.PubMedCrossRefGoogle Scholar
  110. 110.
    Comincini S, Allavena G, Palumbo S, Morini M, Durando F, Angeletti F, et al. microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells. Cancer Biol Ther. 2013;14:574–86.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Gwak HS, Kim TH, Jo GH, Kim YJ, Kwak HJ, Kim JH, et al. Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines. PLoS One. 2012;7, e47449.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481–6.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Hsieh CH, Rau CS, Jeng SF, Lin CJ, Chen YC, Wu CJ, et al. Identification of the potential target genes of microRNA-146a induced by PMA treatment in human microvascular endothelial cells. Exp Cell Res. 2010;316:1119–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Silvia Palumbo
    • 1
  • G. Belmonte
    • 2
  • Paolo Tini
    • 3
    • 4
  • Marzia Toscano
    • 5
    • 3
  • Clelia Miracco
    • 3
    • 6
  • Sergio Comincini
    • 7
    Email author
  1. 1.Unit of Radiation Oncology, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  2. 2.Tuscany Tumor Institute Unit of Radiation Oncology, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  3. 3.Tuscany Tumor InstituteFlorenceItaly
  4. 4.Unit of Radiation OncologyUniversity Hospital of Siena (Azienda Ospedaliera-Universitaria Senese)SienaItaly
  5. 5.Unit of Radiation Oncology, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  6. 6.Unit of Pathological Anatomy, Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  7. 7.Department of Biology and BiotechnologyUniversity of PaviaPaviaItaly

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