Document Type : Review Article


1 Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Science, Shahrekord, Iran

3 Department of Clinical Biochemistry, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

4 Jahad Daneshgahi Research Committee, Jahad Daneshgahi Institute, Mashhad, Iran

5 Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Glioblastoma is a type of brain cancer with aggressive and invasive nature. Such features result from increased proliferation and migration and also poor apoptosis of glioma cells leading to resistance to current treatments such as chemotherapy and radiotherapy. In recent studies, micro RNAs have been introduced as a novel target for treating glioblastoma via regulation of apoptotic signaling pathway, remarkably PI3K/AKT, which affect cellular functions and blockage or progression of the tumor. In this review, we focus on PI3K/AKT signaling pathway and other related apoptotic processes contributing to glioblastoma and investigate the role of micro RNAs interfering in apoptosis, invasion and proliferation of glioma through such apoptotic processes pathways. Databases NCBI, PubMed, and Web of Science were searched for published English articles using keywords such as 'miRNA OR microRNA', 'Glioblastoma', 'apoptotic pathways', 'PI3K and AKT', 'Caspase signaling Pathway' and 'Notch pathway'. Most articles were published from 7 May 2015 to 16 June 2020. This study focused on PI3K/AKT signaling pathway affecting glioma cells in separated subparts. Also, other related apoptotic pathways as the Caspase cycle and Notch have been also investigated. Nearly 40 miRNAs were found as tumor suppressors or onco-miRNA, and their targets, which regulated subcomponents participating in proliferation, invasion, and apoptosis of the tumoral cells. Our review reveals that miRNAs affect key molecules in signaling apoptotic pathways, partly PI3K/AKT, making them potential therapeutic targets to overcome the tumor. However, their utility as a novel treatment for glioblastoma requires further examination and investigation.
# Roshanak Ghaffarian Zirak and Hurie Tajik are equally the first authors.


Main Subjects

  1. Kleihues P, Sobin LH. World Health Organization classification of tumors. Cancer. 2000;88 (12): [DOI:10.1002/1097-0142(20000615)88:123.0.CO;2-F]
  2. 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(2):97-109. [DOI:10.1007/s00401-007-0243-4] [PMID] [PMCID]
  3. Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299-312. [DOI:10.3322/caac.21613] [PMID]
  4. Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109(1):93-108. [DOI:10.1007/s00401-005-0991-y] [PMID]
  5. Burnet NG, Lynch AG, Jefferies SJ, Price SJ, Jones PH, Antoun NM, et al. High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiother Oncol. 2007;85(3):371-8. [DOI:10.1016/j.radonc.2007.10.008] [PMID]
  6. Wesseling P, Capper D. WHO 2016 Classification of gliomas. Neuropathol Appl Neurobiol. 2018;44 (2):139-50. [DOI:10.1111/nan.12432] [PMID]
  7. Lawler S, Chiocca EA. Emerging functions of microRNAs in glioblastoma. J Neurooncol. 2009;92(3):297-306. [DOI:10.1007/s11060-009-9843-2] [PMID]
  8. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell. 2016;164(3):550-63. [PMID] [PMCID] [DOI:10.1016/j.cell.2015.12.028]
  9. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29(12):1203-17. [DOI:10.1101/gad.261982.115] [PMID] [PMCID]
  10. Xie H, Shi S, Chen Q, Chen Z. LncRNA TRG-AS1 promotes glioblastoma cell proliferation by competitively binding with miR-877-5p to regulate SUZ12 expression. Pathol Res Pract. 2019;215(8):152476. [DOI:10.1016/j.prp.2019.152476] [PMID]
  11. Novakova J, Slaby O, Vyzula R, Michalek J. MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun. 2009;386(1):1-5. [DOI:10.1016/j.bbrc.2009.06.034] [PMID]
  12. Huang S-w, Zhong L, Shi J. MicroRNAs as biomarkers for human glioblastoma: progress and potential. Acta Pharmacol Sin. 2018;39(9):1405-13. [DOI:10.1038/aps.2017.173] [PMID] [PMCID]
  13. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-97. [DOI:10.1016/S0092-8674(04)00045-5]
  14. German MA, Pillay M, Jeong D-H, Hetawal A, Luo S, Janardhanan P, et al. Global identification of microRNA-target RNA pairs by parallel analysis of RNA ends. Nature Biotechnol. 2008;26(8):941-6. [DOI:10.1038/nbt1417] [PMID]
  15. Zhang J, Lv J, Zhang F, Che H, Liao Q, Huang W, et al. MicroRNA-211 expression is down-regulated and associated with poor prognosis in human glioma. J Neuro-oncol. 2017;133(3):553-9. [DOI:10.1007/s11060-017-2464-2] [PMID]
  16. Wang N, Zhang Y, Liang H. MicroRNA-598 Inhibits Cell Proliferation and Invasion of Glioblastoma by Directly Targeting Metastasis Associated in Colon Cancer-1 (MACC1). Oncol Res. 2018;26(8):1275-83. [DOI:10.3727/096504018X15185735627746] [PMID] [PMCID]
  17. García MA, Carrasco E, Ramírez A, Jiménez G, López-Ruiz E, Perán M, et al. Apoptosis as a therapeutic target in Cancer and Cancer stem cells: novel strategies and futures perspectives. Apoptosis and medicine: IntechOpen; 2012.
  18. Zhang CZ, Zhang JX, Zhang AL, Shi ZD, Han L, Jia ZF, et al. MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol Cancer. 2010;9(1):229. [DOI:10.1186/1476-4598-9-229] [PMID] [PMCID]
  19. Fu X, Tian J, Zhang L, Chen Y, Hao Q. Involvement of microRNA-93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cells. FEBS Lett. 2012;586 (9):1279-86. [DOI:10.1016/j.febslet.2012.03.006] [PMID]
  20. Yoshizawa A, Fukuoka J, Shimizu S, Shilo K, Franks TJ, Hewitt SM, et al. Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res. 2010;16(1):240-8. [PMCID] [DOI:10.1158/1078-0432.CCR-09-0986] [PMID]
  21. Slattery ML, Mullany LE, Sakoda LC, Wolff RK, Stevens JR, Samowitz WS, et al. The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer. Mol Carcinog. 2018;57(2):243-61. [DOI:10.1002/mc.22752] [PMID] [PMCID]
  22. Gu JJ, Fan KC, Zhang JH, Chen HJ, Wang SS. Suppression of microRNA-130b inhibits glioma cell proliferation and invasion, and induces apoptosis by PTEN/AKT signaling. Int J Mol Med. 2018;41(1):284-92. [DOI:10.3892/ijmm.2017.3233]
  23. Xu X, Zhang Y, Qu D, Jiang T, Li S. Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res. 2011;30(1):33. [DOI:10.1186/1756-9966-30-33] [PMID] [PMCID]
  24. Møller HG, Rasmussen AP, Andersen HH, Johnsen KB, Henriksen M, Duroux M. A systematic review of microRNA in glioblastoma multiforme: micro-modulators in the mesenchymal mode of migration and invasion. Molecular Neurobiol. 2013;47(1):131-44. [DOI:10.1007/s12035-012-8349-7] [PMID] [PMCID]
  25. Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, et al. Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer. 1994;56(1):72-7. [DOI:10.1002/ijc.2910560114] [PMID]
  26. Dai Z, Wang L, Wang X, Zhao B, Zhao W, Bhardwaj SS, et al. Oxymatrine induces cell cycle arrest and apoptosis and suppresses the invasion of human glioblastoma cells through the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3. Oncol Rep. 2018;40(2):867-76. [DOI:10.3892/or.2018.6512] [PMID]
  27. Padfield E, Ellis HP, Kurian KM. Current Therapeutic Advances Targeting EGFR and EGFRvIII in Glioblastoma. Front Oncol. 2015;5:5. [DOI:10.3389/fonc.2015.00005] [PMID] [PMCID]
  28. Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther. 2009;8(2):386-93. [DOI:10.1158/1535-7163.MCT-08-0680] [PMID] [PMCID]
  29. Liu Z, Jiang Z, Huang J, Huang S, Li Y, Yu S, et al. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int J Oncol. 2014; 44(5):1571-80. [DOI:10.3892/ijo.2014.2322] [PMID]
  30. Wu DG, Wang YY, Fan LG, Luo H, Han B, Sun LH, et al. MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression. Chin Med J (Engl). 2011;124(17): 2616-21.
  31. Chu SH, Feng DF, Zhang H, Chen ET, Duan ZX, Li XY, et al. c-Met-targeted RNA interference inhibits growth and metastasis of glioma U251 cells in vitro. J Neurooncol. 2009;93(2):183-9. [DOI:10.1007/s11060-008-9772-5] [PMID]
  32. Giglio S, Vecchione A. c-Met and miRs in Cancer. Biomed. 2015;3(1):32-44. [DOI:10.3390/biomedicines3010032] [PMID] [PMCID]
  33. Yao Y, Dou C, Lu Z, Zheng X, Liu Q. MACC1 suppresses cell apoptosis in hepatocellular carcinoma by targeting the HGF/c-MET/AKT pathway. Cell Physiol Biochem. 2015;35(3):983-96. [DOI:10.1159/000369754] [PMID]
  34. Zhen L, Yun-Hui L, Hong-Yu D, Jun M, Yi-Long Y. Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c-Met axis. Tumour Biol. 2016;37(1):673-83. [DOI:10.1007/s13277-015-3843-y] [PMID]
  35. Chen L, Zhang J, Feng Y, Li R, Sun X, Du W, et al. MiR-410 regulates MET to influence the proliferation and invasion of glioma. Int J Biochem Cell Biol. 2012;44(11):1711-7. [DOI:10.1016/j.biocel.2012.06.027] [PMID]
  36. Salvi A, Sabelli C, Moncini S, Venturin M, Arici B, Riva P, et al. MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS J. 2009;276(11):2966-82. [DOI:10.1111/j.1742-4658.2009.07014.x] [PMID]
  37. Nie X, Su Z, Yan R, Yan A, Qiu S, Zhou Y. MicroRNA-562 negatively regulated c-MET/AKT pathway in the growth of glioblastoma cells. Onco Targets Ther. 2019;12:41-9. [DOI:10.2147/OTT.S186701] [PMID] [PMCID]
  38. Dai C, Xie Y, Zhuang X, Yuan Z. MiR-206 inhibits epithelial ovarian cancer cells growth and invasion via blocking c-Met/AKT/mTOR signaling pathway. Biomed Pharmacother. 2018; 104:763-70. [DOI:10.1016/j.biopha.2018.05.077] [PMID]
  39. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655-7. [DOI:10.1126/science.296.5573.1655] [PMID]
  40. Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008;27(41):5416-30. [DOI:10.1038/onc.2008.239] [PMID]
  41. Koul D. PTEN signaling pathways in glioblastoma. Cancer Biol Ther. 2008;7(9):1321-5. [DOI:10.4161/cbt.7.9.6954] [PMID]
  42. Lee J, Kim B, Park M, Lee Y, Kim Y, Lee B, et al. PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation. Cell Death Differ. 2011;18 (4):666-77. [DOI:10.1038/cdd.2010.139] [PMID] [PMCID]
  43. Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, et al. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009;23(11):1327-37. [DOI:10.1101/gad.1777409] [PMID] [PMCID]
  44. Hu X, Chen D, Cui Y, Li Z, Huang J. Targeting microRNA-23a to inhibit glioma cell invasion via HOXD10. Sci Rep. 2013;3(1):3423. [DOI:10.1038/srep03423] [PMID] [PMCID]
  45. Xia X, Li Y, Wang W, Tang F, Tan J, Sun L, et al. MicroRNA-1908 functions as a glioblastoma oncogene by suppressing PTEN tumor suppressor pathway. Mol Cancer. 2015;14(1):1-14. [PMID] [PMCID] [DOI:10.1186/s12943-015-0423-0]
  46. Jin S, Dai Y, Li C, Fang X, Han H, Wang D. MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7. Am J Transl Res. 2016;8(4): 1826-37.
  47. Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. Int J Oncol. 2005;26 (3):641-8. [DOI:10.3892/ijo.26.3.641] [PMID]
  48. Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell. 2005; 7(3):263-73. [DOI:10.1016/j.ccr.2005.02.010] [PMID]
  49. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110. [PMID] [PMCID] [DOI:10.1016/j.ccr.2009.12.020]
  50. Mao H, Lebrun DG, Yang J, Zhu VF, Li M. Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest. 2012;30(1):48-56. [DOI:10.3109/07357907.2011.630050] [PMID] [PMCID]
  51. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55(3):178-94. [DOI:10.3322/canjclin.55.3.178] [PMID]
  52. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22(56):8983-98. [DOI:10.1038/sj.onc.1207115] [PMID]
  53. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13(22):2905-27. [DOI:10.1101/gad.13.22.2905] [PMID]
  54. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2): 274-93. [PMID] [PMCID] [DOI:10.1016/j.cell.2012.03.017]
  55. Fan Q-W, Weiss WA. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. mTOR: Springer; 2012. p. 349-59. [DOI:10.1007/978-1-61779-430-8_22] [PMID] [PMCID]
  56. Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010;7(3):264-74. [DOI:10.1016/j.nurt.2010.05.005] [PMID] [PMCID]
  57. Sun S-Y. mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett. 2013;340(1):1-8. [PMID] [PMCID] [DOI:10.1016/j.canlet.2013.06.017]
  58. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125-37. [DOI:10.1016/j.cell.2006.08.033] [PMID]
  59. Lisi L, Laudati E, Navarra P, Dello Russo C. The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype. J Neuroinflammation. 2014;11(1):125. [PMID] [PMCID] [DOI:10.1186/1742-2094-11-125]
  60. Kalhori MR, Irani S, Soleimani M, Arefian E, Kouhkan F. The effect of miR-579 on the PI3K/AKT pathway in human glioblastoma PTEN mutant cell lines. J Cell Biochem. 2019;120(10): 16760-74. [DOI:10.1002/jcb.28935] [PMID]
  61. Ehsan A, Fereshteh FA, Kaveh K, Masoud S. miR-548x and miR-4698 controlled cell proliferation by affecting the PI3K/AKT signaling pathway in Glioblastoma cell lines. Sci Rep. 2020;10(1). [DOI:10.1038/s41598-020-57588-5] [PMID] [PMCID]
  62. Zhou Y, An H, Wu G. MicroRNA-6071 Suppresses Glioblastoma Progression Through the Inhibition of PI3K/AKT/mTOR Pathway by Binding to ULBP2. OncoTargets Ther. 2020;13:9429. [DOI:10.2147/OTT.S265791] [PMID] [PMCID]
  63. Li Y, Ma X, Wang Y, Li G. miR-489 inhibits proliferation, cell cycle progression and induces apoptosis of glioma cells via targeting SPIN1-mediated PI3K/AKT pathway. Biomed Pharmacother. 2017;93:435-43. [DOI:10.1016/j.biopha.2017.06.058] [PMID]
  64. Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro-oncology. 2010;12(11):1102-12. [DOI:10.1093/neuonc/noq080] [PMID] [PMCID]
  65. Yang H, Song Z, Wu X, Wu Y, Liu C. MicroRNA-652 suppresses malignant phenotypes in glioblastoma multiforme via FOXK1-mediated AKT/mTOR signaling pathway. Onco Targets Ther. 2019;12:5563-75. [DOI:10.2147/OTT.S204715] [PMID] [PMCID]
  66. Cui Y, Zhao J, Yi L, Jiang Y. microRNA-153 Targets mTORC2 Component Rictor to Inhibit Glioma Cells. PloS one. 2016;11(6):e0156915. [DOI:10.1371/journal.pone.0156915] [PMID] [PMCID]
  67. Chen PH, Cheng CH, Shih CM, Ho KH, Lin CW, Lee CC, et al. The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death. PloS one. 2016;11(11):e0167096. [PMCID] [DOI:10.1371/journal.pone.0167096] [PMID]
  68. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016;7(22):33440-50. [PMID] [PMCID] [DOI:10.18632/oncotarget.7961]
  69. Luo G, Luo W, Sun X, Lin J, Wang M, Zhang Y, et al. MicroRNA‑21 promotes migration and invasion of glioma cells via activation of Sox2 and β‑catenin signaling. Mol Med Rep. 2017;15(1):187-93. [DOI:10.3892/mmr.2016.5971] [PMID] [PMCID]
  70. Young MR, Santhanam AN, Yoshikawa N, Colburn NH. Have tumor suppressor PDCD4 and its counteragent oncogenic miR-21 gone rogue? Mol Interv. 2010;10(2):76. [DOI:10.1124/mi.10.2.5] [PMID] [PMCID]
  71. Gaur AB, Holbeck SL, Colburn NH, Israel MA. Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro Oncol. 2011;13(6):580-90. [DOI:10.1093/neuonc/nor033] [PMID] [PMCID]
  72. Rajesh Y, Pal I, Banik P, Chakraborty S, Borkar SA, Dey G, et al. Insights into molecular therapy of glioma: current challenges and next generation blueprint. Acta Pharmacol Sin. 2017;38(5):591-613. [DOI:10.1038/aps.2016.167] [PMID] [PMCID]
  73. Nasr Z, Pelletier J. Tumor progression and metastasis: role of translational deregulation. Anticancer Res. 2012;32(8):3077-84.
  74. Guo P, Yu Y, Li H, Zhang D, Gong A, Li S, et al. TGF-β1-induced miR-503 controls cell growth and apoptosis by targeting PDCD4 in glioblastoma cells. Sci Rep. 2017;7(1):1-10. [DOI:10.1038/s41598-017-11885-8] [PMID] [PMCID]
  75. Ma QQ, Huang JT, Xiong YG, Yang XY, Han R, Zhu WW. MicroRNA-96 Regulates Apoptosis by Targeting PDCD4 in Human Glioma Cells. Technol Cancer Res Treat. 2017;16(1):92-8. [DOI:10.1177/1533034616629260] [PMID] [PMCID]
  76. Suh SS, Yoo JY, Nuovo GJ, Jeon YJ, Kim S, Lee TJ, et al. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. Proc Natl Acad Sci U S A. 2012;109(14):5316-21. [DOI:10.1073/pnas.1202465109] [PMID] [PMCID]
  77. Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, et al. Bimodal regulation of FoxO3 by AKT and 14-3-3. Biochim Biophys Acta. 2011;1813(8):1453-64. [DOI:10.1016/j.bbamcr.2011.05.001] [PMID] [PMCID]
  78. Liu N, Tu Y. Systematic review of microRNAs and its therapeutic potential in glioma. Cancer Transll Med. 2015;1(2):50. [DOI:10.4103/2395-3977.155924]
  79. Tivnan A, Foley NH, Tracey L, Davidoff AM, Stallings RL. MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma. Anticancer Res. 2010;30(11):4391-5.
  80. Zhang C, Wang G, Kang C, Du Y, Pu P. [Up-regulation of p27(kip1) by miR-221/222 antisense oligonucleotides enhances the radiosensitivity of U251 glioblastoma]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2009;26(6):634-8.
  81. Gillies JK, Lorimer IA. Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle. 2007;6(16):2005-9. [DOI:10.4161/cc.6.16.4526] [PMID]
  82. Guan H, Song L, Cai J, Huang Y, Wu J, Yuan J, et al. Sphingosine kinase 1 regulates the Akt/FOXO3a/Bim pathway and contributes to apoptosis resistance in glioma cells. PloS one. 2011;6(5):e19946. [PMID] [PMCID] [DOI:10.1371/journal.pone.0019946]
  83. Gabriely G, Teplyuk NM, Krichevsky AM. Context effect: microRNA-10b in cancer cell proliferation, spread and death. Autophagy. 2011;7(11):1384-6. [DOI:10.4161/auto.7.11.17371] [PMID]
  84. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci. 2007;104 (2):618-23. [PMID] [PMCID] [DOI:10.1073/pnas.0606599104]
  85. Cao Y, Lathia JD, Eyler CE, Wu Q, Li Z, Wang H, et al. Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer. 2010;1(1):50-61. [DOI:10.1177/1947601909356352] [PMID] [PMCID]
  86. Wei J, Wang F, Kong L-Y, Xu S, Doucette T, Ferguson SD, et al. MiR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res. 2013;73 (13):3913-26. [DOI:10.1158/0008-5472.CAN-12-4318] [PMID] [PMCID]
  87. Han L, Yue X, Zhou X, Lan FM, You G, Zhang W, et al. MicroRNA‐21 expression is regulated by β‐catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK. CNS Neurosci Ther. 2012;18(7):573-83. [DOI:10.1111/j.1755-5949.2012.00344.x] [PMID] [PMCID]
  88. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635-47. [DOI:10.1016/j.cell.2005.01.014] [PMID]
  89. Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell. 2002;109(2):S81-S96. [DOI:10.1016/S0092-8674(02)00703-1]
  90. Zhang G, Chen L, Khan AA, Li B, Gu B, Lin F, et al. miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis. Int J Cancer. 2018;143 (3):635-44. [DOI:10.1002/ijc.31329] [PMID]
  91. Song L, Huang Q, Chen K, Liu L, Lin C, Dai T, et al. miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-beta. Biochem Biophys Res Commun. 2010;402 (1):135-40. [DOI:10.1016/j.bbrc.2010.10.003] [PMID]
  92. Asuthkar S, Velpula KK, Chetty C, Gorantla B, Rao JS. Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity. Oncotarget. 2012;3(11):1439-54. [PMID] [PMCID] [DOI:10.18632/oncotarget.683]
  93. Yang TQ, Lu XJ, Wu TF, Ding DD, Zhao ZH, Chen GL, et al. Micro RNA‐16 inhibits glioma cell growth and invasion through suppression of BCL 2 and the nuclear factor‐κB1/MMP 9 signaling pathway. Cancer Sci. 2014;105(3):265-71. [DOI:10.1111/cas.12351] [PMID] [PMCID]
  94. Sun L, Yan W, Wang Y, Sun G, Luo H, Zhang J, et al. MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10. Brain Res. 2011;1389:9-18. [DOI:10.1016/j.brainres.2011.03.013] [PMID]
  95. Xu X, Yang H, Wang X, Tu Y. The significance of nuclear factor-kappa B signaling pathway in glioma: A review. Cancer Transll Med. 2017;3(5):181. [DOI:10.4103/ctm.ctm_48_16]
  96. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30 (1):87. [DOI:10.1186/1756-9966-30-87] [PMID] [PMCID]
  97. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49-63. [DOI:10.1038/nrm3722] [PMID]
  98. Ghaemi S, Arefian E, Rezazadeh Valojerdi R, Soleimani M, Moradimotlagh A, Jamshidi Adegani F. Inhibiting the expression of anti-apoptotic genes BCL2L1 and MCL1, and apoptosis induction in glioblastoma cells by microRNA-342. Biomed Pharmacother. 2020; 121:109641. [DOI:10.1016/j.biopha.2019.109641] [PMID]
  99. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843-50. [DOI:10.1074/jbc.M109745200] [PMID]
  100. Zhang J, Jiang H, Shao J, Mao R, Liu J, Ma Y, et al. SOX4 inhibits GBM cell growth and induces G0/G1 cell cycle arrest through Akt-p53 axis. BMC Neurol. 2014;14(1):207. [PMID] [PMCID] [DOI:10.1186/s12883-014-0207-y]
  101. Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer. 2002;2(8):594-604. [DOI:10.1038/nrc864] [PMID]
  102. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995;82(4):675-84. [DOI:10.1016/0092-8674(95)90039-X]
  103. Yuan L, Zhang Y, Xia J, Liu B, Zhang Q, Liu J, et al. Resveratrol induces cell cycle arrest via a p53-independent pathway in A549 cells. Mol Med Rep. 2015;11(4):2459-64. [DOI:10.3892/mmr.2014.3100] [PMID] [PMCID]
  104. Feng R, Dong L. Knockdown of microRNA-127 reverses adriamycin resistance via cell cycle arrest and apoptosis sensitization in adriamycin-resistant human glioma cells. Int J Clin Exp Pathol. 2015;8(6):6107-16.
  105. Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008;68(19):8164-72. [DOI:10.1158/0008-5472.CAN-08-1305] [PMID]
  106. Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27(48):6194-206. [DOI:10.1038/onc.2008.297] [PMID]
  107. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17(6):1675-87. [DOI:10.1093/emboj/17.6.1675] [PMID] [PMCID]
  108. Gdynia G, Grund K, Eckert A, Bock BC, Funke B, Macher-Goeppinger S, et al. Basal caspase activity promotes migration and invasiveness in glioblastoma cells. Mol Cancer Res. 2007;5 (12):1232-40. [DOI:10.1158/1541-7786.MCR-07-0343] [PMID]
  109. Lavrik I, Golks A, Krammer PH. Death receptor signaling. J Cell Sci. 2005;118(Pt 2):265-7. [DOI:10.1242/jcs.01610] [PMID]
  110. Garofalo M, Condorelli G, Croce C, Condorelli G. MicroRNAs as regulators of death receptors signaling. Cell Death Differ. 2010;17(2):200-8. [DOI:10.1038/cdd.2009.105] [PMID]
  111. Crowder RN, El-Deiry WS. Caspase-8 regulation of TRAIL-mediated cell death. Exp Oncol. 2012;34(3):160-4.
  112. Fulda S. Cell death-based treatment of glioblastoma. Cell Death Dis. 2018;9(2):121. [DOI:10.1038/s41419-017-0021-8] [PMID] [PMCID]
  113. Ola MS, Nawaz M, Ahsan H. Role of Bcl2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011;351(1-2):41-58. [DOI:10.1007/s11010-010-0709-x] [PMID]
  114. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491-501. [DOI:10.1016/S0092-8674(00)81590-1]
  115. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2,-3,-6,-7,-8, and-10 in a caspase-9-dependent manner. J Cell Biol. 1999;144(2):281-92. [DOI:10.1083/jcb.144.2.281] [PMID] [PMCID]
  116. Quintavalle C, Donnarumma E, Iaboni M, Roscigno G, Garofalo M, Romano G, et al. Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells. Oncogene. 2013;32(34):4001-8. [DOI:10.1038/onc.2012.410] [PMID]
  117. Atkinson GP, Nozell SE, Benveniste EN. NF-κB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother. 2010;10(4):575-86. [DOI:10.1586/ern.10.21] [PMID] [PMCID]
  118. Valdés-Rives SA, Casique-Aguirre D, Germán-Castelán L, Velasco-Velázquez MA, González-Arenas A. Apoptotic signaling pathways in glioblastoma and therapeutic implications. BioMed Res Int. 2017;2017. [DOI:10.1155/2017/7403747] [PMID] [PMCID]
  119. Sana J, Hajduch M, Michalek J, Vyzula R, Slaby O. MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications. J Cell Mol Med. 2011;15(8):1636-44. [DOI:10.1111/j.1582-4934.2011.01317.x] [PMID] [PMCID]
  120. Haemmig S, Baumgartner U, Gluck A, Zbinden S, Tschan MP, Kappeler A, et al. miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas. Cell Death Dis. 2014;5(6):e1279. [DOI:10.1038/cddis.2014.245] [PMID] [PMCID]
  121. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-89. [DOI:10.1038/nrm2009] [PMID]
  122. Wei J, Hemmings GP. The NOTCH4 locus is associated with susceptibility to schizophrenia. Nature Genetics. 2000;25(4):376-7. [DOI:10.1038/78044] [PMID]
  123. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000;101(5):499-510. [DOI:10.1016/S0092-8674(00)80860-0]
  124. Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, et al. Stabilized β-catenin functions through TCF/LEF proteins and the Notch/RBP-Jκ complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol. 2008;28(24):7427-41. [DOI:10.1128/MCB.01962-07] [PMID] [PMCID]
  125. Purow BW, Sundaresan TK, Burdick MJ, Kefas BA, Comeau LD, Hawkinson MP, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis. 2008;29(5):918-25. [DOI:10.1093/carcin/bgn079] [PMID] [PMCID]
  126. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells. 2010;28(1):5-16. [DOI:10.1002/stem.254] [PMID] [PMCID]
  127. Kanamori M, Kawaguchi T, Nigro JM, Feuerstein BG, Berger MS, Miele L, et al. Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg. 2007;106(3):417-27. [DOI:10.3171/jns.2007.106.3.417] [PMID]
  128. Banelli B, Forlani A, Allemanni G, Morabito A, Pistillo MP, Romani M. MicroRNA in Glioblastoma: An Overview. Int J Genomics. 2017;2017:7639084. [DOI:10.1155/2017/7639084] [PMID] [PMCID]
  129. Bhaumik D, Scott G, Schokrpur S, Patil C, Campisi J, Benz C. Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008;27(42):5643-7. [DOI:10.1038/onc.2008.171] [PMID] [PMCID]
  130. Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, et al. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle. 2010;9(6):1031-6. [DOI:10.4161/cc.9.6.10987] [PMID] [PMCID]
  131. Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R, et al. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008;582(10):1564-8. [DOI:10.1016/j.febslet.2008.03.057] [PMID]
  132. Shi L, Wang Z, Sun G, Wan Y, Guo J, Fu X. miR-145 inhibits migration and invasion of glioma stem cells by targeting ABCG2. Neuromolecular Med. 2014;16(2):517-28. [DOI:10.1007/s12017-014-8305-y] [PMID]
  133. Burton T, Henson E, Azad M, Brown M, Eisenstat D, Gibson S. BNIP3 acts as transcriptional repressor of death receptor-5 expression and prevents TRAIL-induced cell death in gliomas. Cell Death Dis. 2013;4(4):e587-e. [DOI:10.1038/cddis.2013.100] [PMID] [PMCID]