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Cancers  2012 

A microRNA Link to Glioblastoma Heterogeneity

DOI: 10.3390/cancers4030846

Keywords: glioma, glioblastoma, microRNA, angiogenesis, glioma stem cells, metabolism, Warburg effect

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Abstract:

Glioblastomas (GBM) are one of the most malignant adult primary brain tumors. Through decades of research using various model systems and GBM patients, we have gained considerable insights into the mechanisms regulating GBM pathogenesis, but have mostly failed to significantly improve clinical outcome. For the most part GBM heterogeneity is responsible for this lack of progress. Here, we have discussed sources of cellular and microenvironmental heterogeneity in GBMs and their potential regulation through microRNA mediated mechanisms. We have focused on the role of individual microRNAs (miRNA) through their specific targets and miRNA mediated RNA-RNA interaction networks with the potential to influence various aspects of GBM heterogeneity including tumor neo-vascularization. We believe a better understanding of such mechanisms for regulation of GBM pathogenesis will be instrumental for future therapeutic options.

References

[1]  Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674, doi:10.1016/j.cell.2011.02.013.
[2]  Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-Year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009, 10, 459–466, doi:10.1016/S1470-2045(09)70025-7.
[3]  Hjelmeland, A.B.; Lathia, J.D.; Sathornsumetee, S.; Rich, J.N. Twisted tango: Brain tumor neurovascular interactions. Nat. Neurosci. 2011, 14, 1375–1381.
[4]  Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444, 756–760.
[5]  Bao, S.; Wu, Q.; Sathornsumetee, S.; Hao, Y.; Li, Z.; Hjelmeland, A.B.; Shi, Q.; McLendon, R.E.; Bigner, D.D.; Rich, J.N. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006, 66, 7843–7848.
[6]  Calabrese, C.; Poppleton, H.; Kocak, M.; Hogg, T.L.; Fuller, C.; Hamner, B.; Oh, E.Y.; Gaber, M.W.; Finklestein, D.; Allen, M.; et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007, 11, 69–82, doi:10.1016/j.ccr.2006.11.020.
[7]  Folkins, C.; Shaked, Y.; Man, S.; Tang, T.; Lee, C.R.; Zhu, Z.; Hoffman, R.M.; Kerbel, R.S. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res. 2009, 69, 7243–7251.
[8]  Gilbertson, R.J.; Rich, J.N. Making a tumour’s bed: Glioblastoma stem cells and the vascular niche. Nat. Rev. Cancer 2007, 7, 733–736, doi:10.1038/nrc2246.
[9]  Heddleston, J.M.; Li, Z.; McLendon, R.E.; Hjelmeland, A.B.; Rich, J.N. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009, 8, 3274–3284.
[10]  Li, Z.; Bao, S.; Wu, Q.; Wang, H.; Eyler, C.; Sathornsumetee, S.; Shi, Q.; Cao, Y.; Lathia, J.; McLendon, R.E.; et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009, 15, 501–513.
[11]  Liu, G.; Yuan, X.; Zeng, Z.; Tunici, P.; Ng, H.; Abdulkadir, I.R.; Lu, L.; Irvin, D.; Black, K.L.; Yu, J.S. Analysis of gene expression and chemoresistance of cd133+ cancer stem cells in glioblastoma. Mol. Cancer 2006, 5, 67, doi:10.1186/1476-4598-5-67.
[12]  Salmaggi, A.; Boiardi, A.; Gelati, M.; Russo, A.; Calatozzolo, C.; Ciusani, E.; Sciacca, F.L.; Ottolina, A.; Parati, E.A.; La Porta, C.; et al. Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 2006, 54, 850–860, doi:10.1002/glia.20414.
[13]  Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401.
[14]  Pistollato, F.; Abbadi, S.; Rampazzo, E.; Persano, L.; Della Puppa, A.; Frasson, C.; Sarto, E.; Scienza, R.; D’Avella, D.; Basso, G. Intratumoral hypoxic gradient drives stem cells distribution and mgmt expression in glioblastoma. Stem Cells 2010, 28, 851–862.
[15]  Baylin, S.B.; Jones, P.A. A decade of exploring the cancer epigenome—Biological and translational implications. Nat. Rev. Cancer 2011, 11, 726–734, doi:10.1038/nrc3130.
[16]  Nowell, P.C. The clonal evolution of tumor cell populations. Science 1976, 194, 23–28.
[17]  Bissell, M.J.; Hines, W.C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 2011, 17, 320–329, doi:10.1038/nm.2328.
[18]  Magee, J.A.; Piskounova, E.; Morrison, S.J. Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell 2012, 21, 283–296, doi:10.1016/j.ccr.2012.03.003.
[19]  Dick, J.E. Stem cell concepts renew cancer research. Blood 2008, 112, 4793–4807.
[20]  Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105–111.
[21]  Shackleton, M.; Quintana, E.; Fearon, E.R.; Morrison, S.J. Heterogeneity in cancer: Cancer stem cells versus clonal evolution. Cell 2009, 138, 822–829, doi:10.1016/j.cell.2009.08.017.
[22]  Eramo, A.; Ricci-Vitiani, L.; Zeuner, A.; Pallini, R.; Lotti, F.; Sette, G.; Pilozzi, E.; Larocca, L.M.; Peschle, C.; de Maria, R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006, 13, 1238–1241, doi:10.1038/sj.cdd.4401872.
[23]  Galli, R.; Binda, E.; Orfanelli, U.; Cipelletti, B.; Gritti, A.; de Vitis, S.; Fiocco, R.; Foroni, C.; Dimeco, F.; Vescovi, A. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004, 64, 7011–7021, doi:10.1158/0008-5472.CAN-04-1364.
[24]  Sanai, N.; Alvarez-Buylla, A.; Berger, M.S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 2005, 353, 811–822.
[25]  Charles, N.; Ozawa, T.; Squatrito, M.; Bleau, A.M.; Brennan, C.W.; Hambardzumyan, D.; Holland, E.C. Perivascular nitric oxide activates notch signaling and promotes stem-like character in pdgf-induced glioma cells. Cell Stem Cell 2010, 6, 141–152, doi:10.1016/j.stem.2010.01.001.
[26]  Hambardzumyan, D.; Becher, O.J.; Rosenblum, M.K.; Pandolfi, P.P.; Manova-Todorova, K.; Holland, E.C. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008, 22, 436–448.
[27]  Wu, A.; Wei, J.; Kong, L.Y.; Wang, Y.; Priebe, W.; Qiao, W.; Sawaya, R.; Heimberger, A.B. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neurooncology 2010, 12, 1113–1125.
[28]  Deleyrolle, L.P.; Harding, A.; Cato, K.; Siebzehnrubl, F.A.; Rahman, M.; Azari, H.; Olson, S.; Gabrielli, B.; Osborne, G.; Vescovi, A.; et al. Evidence for label-retaining tumour-initiating cells in human glioblastoma. Brain 2011, 134, 1331–1343, doi:10.1093/brain/awr081.
[29]  Knizetova, P.; Ehrmann, J.; Hlobilkova, A.; Vancova, I.; Kalita, O.; Kolar, Z.; Bartek, J. Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the vegf-vegfr2 (kdr) interplay. Cell Cycle 2008, 7, 2553–2561.
[30]  Aboody, K.S.; Brown, A.; Rainov, N.G.; Bower, K.A.; Liu, S.; Yang, W.; Small, J.E.; Herrlinger, U.; Ourednik, V.; Black, P.M.; et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc. Natl. Acad. Sci. USA 2000, 97, 12846–12851.
[31]  Assanah, M.C.; Bruce, J.N.; Suzuki, S.O.; Chen, A.; Goldman, J.E.; Canoll, P. PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain. Glia 2009, 57, 1835–1847, doi:10.1002/glia.20895.
[32]  Charles, N.A.; Holland, E.C.; Gilbertson, R.; Glass, R.; Kettenmann, H. The brain tumor microenvironment. Glia 2011, 59, 1169–1180, doi:10.1002/glia.21136.
[33]  Chirasani, S.R.; Sternjak, A.; Wend, P.; Momma, S.; Campos, B.; Herrmann, I.M.; Graf, D.; Mitsiadis, T.; Herold-Mende, C.; Besser, D.; et al. Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain 2010, 133, 1961–1972, doi:10.1093/brain/awq128.
[34]  Walzlein, J.H.; Synowitz, M.; Engels, B.; Markovic, D.S.; Gabrusiewicz, K.; Nikolaev, E.; Yoshikawa, K.; Kaminska, B.; Kempermann, G.; Uckert, W.; et al. The antitumorigenic response of neural precursors depends on subventricular proliferation and age. Stem Cells 2008, 26, 2945–2954, doi:10.1634/stemcells.2008-0307.
[35]  Sanai, N.; Nguyen, T.; Ihrie, R.A.; Mirzadeh, Z.; Tsai, H.H.; Wong, M.; Gupta, N.; Berger, M.S.; Huang, E.; Garcia-Verdugo, J.M.; et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 2011, 478, 382–386.
[36]  Dwain, I.; Xiangpeng, Y.; Zeng, Z.; Patricia, T.; Joh, S.Y. Neural stem cells—A promising potential therapy for brain tumors. Curr. Stem Cell Res. Ther. 2006, 1, 79–84, doi:10.2174/157488806775269070.
[37]  Mokry, J.; Cizkova, D.; Filip, S.; Ehrmann, J.; Osterreicher, J.; Kolar, Z.; English, D. Nestin expression by newly formed human blood vessels. Stem Cells Dev. 2004, 13, 658–664.
[38]  Ricci-Vitiani, L.; Pallini, R.; Biffoni, M.; Todaro, M.; Invernici, G.; Cenci, T.; Maira, G.; Parati, E.A.; Stassi, G.; Larocca, L.M.; et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010, 468, 824–828.
[39]  Soda, Y.; Marumoto, T.; Friedmann-Morvinski, D.; Soda, M.; Liu, F.; Michiue, H.; Pastorino, S.; Yang, M.; Hoffman, R.M.; Kesari, S.; et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc. Natl. Acad. Sci. USA 2011, 108, 4274–4280.
[40]  Wang, R.; Chadalavada, K.; Wilshire, J.; Kowalik, U.; Hovinga, K.E.; Geber, A.; Fligelman, B.; Leversha, M.; Brennan, C.; Tabar, V. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010, 468, 829–833.
[41]  Wen, P.Y.; Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 2008, 359, 492–507, doi:10.1056/NEJMra0708126.
[42]  Brat, D.J.; van Meir, E.G. Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: A new world of angiogenesis research. Am. J. Pathol. 2001, 158, 789–796, doi:10.1016/S0002-9440(10)64025-4.
[43]  Zadeh, G.; Koushan, K.; Baoping, Q.; Shannon, P.; Guha, A. Role of angiopoietin-2 in regulating growth and vascularity of astrocytomas. J. Oncol. 2010, 2010, 659231.
[44]  Wesseling, P.; Schlingemann, R.O.; Rietveld, F.J.; Link, M.; Burger, P.C.; Ruiter, D.J. Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: An immuno-light and immuno-electron microscopic study. J. Neuropathol. Exp. Neurol. 1995, 54, 304–310.
[45]  Ahluwalia, M.S.; Gladson, C.L. Progress on antiangiogenic therapy for patients with malignant glioma. J. Oncol. 2010, 2010, 689018.
[46]  Bar, E.E.; Chaudhry, A.; Lin, A.; Fan, X.; Schreck, K.; Matsui, W.; Piccirillo, S.; Vescovi, A.L.; DiMeco, F.; Olivi, A.; et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007, 25, 2524–2533, doi:10.1634/stemcells.2007-0166.
[47]  Becher, O.J.; Hambardzumyan, D.; Fomchenko, E.I.; Momota, H.; Mainwaring, L.; Bleau, A.M.; Katz, A.M.; Edgar, M.; Kenney, A.M.; Cordon-Cardo, C.; et al. Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res. 2008, 68, 2241–2249.
[48]  Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 2007, 17, 165–172, doi:10.1016/j.cub.2006.11.033.
[49]  Takezaki, T.; Hide, T.; Takanaga, H.; Nakamura, H.; Kuratsu, J.; Kondo, T. Essential role of the hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 2011, 102, 1306–1312.
[50]  Dong, J.; Grunstein, J.; Tejada, M.; Peale, F.; Frantz, G.; Liang, W.C.; Bai, W.; Yu, L.; Kowalski, J.; Liang, X.; et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004, 23, 2800–2810.
[51]  Du, R.; Lu, K.V.; Petritsch, C.; Liu, P.; Ganss, R.; Passegue, E.; Song, H.; Vandenberg, S.; Johnson, R.S.; Werb, Z.; et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008, 13, 206–220, doi:10.1016/j.ccr.2008.01.034.
[52]  Hashizume, H.; Baluk, P.; Morikawa, S.; McLean, J.W.; Thurston, G.; Roberge, S.; Jain, R.K.; McDonald, D.M. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 2000, 156, 1363–1380, doi:10.1016/S0002-9440(10)65006-7.
[53]  Morikawa, S.; Baluk, P.; Kaidoh, T.; Haskell, A.; Jain, R.K.; McDonald, D.M. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 2002, 160, 985–1000, doi:10.1016/S0002-9440(10)64920-6.
[54]  Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314.
[55]  Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033.
[56]  Cairns, R.A.; Harris, I.S.; Mak, T.W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 2011, 11, 85–95.
[57]  Christofk, H.R.; Vander Heiden, M.G.; Harris, M.H.; Ramanathan, A.; Gerszten, R.E.; Wei, R.; Fleming, M.D.; Schreiber, S.L.; Cantley, L.C. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008, 452, 230–233.
[58]  Christofk, H.R.; Vander Heiden, M.G.; Wu, N.; Asara, J.M.; Cantley, L.C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 2008, 452, 181–186.
[59]  Wolf, A.; Agnihotri, S.; Micallef, J.; Mukherjee, J.; Sabha, N.; Cairns, R.; Hawkins, C.; Guha, A. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 2011, 208, 313–326, doi:10.1084/jem.20101470.
[60]  Shim, H.; Dolde, C.; Lewis, B.C.; Wu, C.S.; Dang, G.; Jungmann, R.A.; Dalla-Favera, R.; Dang, C.V. c-Myc transactivation of ldh-a: Implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. USA 1997, 94, 6658–6663.
[61]  Fantin, V.R.; St-Pierre, J.; Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006, 9, 425–434, doi:10.1016/j.ccr.2006.04.023.
[62]  Michelakis, E.D.; Sutendra, G.; Dromparis, P.; Webster, L.; Haromy, A.; Niven, E.; Maguire, C.; Gammer, T.L.; Mackey, J.R.; Fulton, D.; et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2010, 2, 31ra34, doi:10.1126/scitranslmed.3000677.
[63]  Snuderl, M.; Fazlollahi, L.; Le, L.P.; Nitta, M.; Zhelyazkova, B.H.; Davidson, C.J.; Akhavanfard, S.; Cahill, D.P.; Aldape, K.D.; Betensky, R.A.; et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011, 20, 810–817.
[64]  Bristow, R.G.; Hill, R.P. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat. Rev. Cancer 2008, 8, 180–192, doi:10.1038/nrc2344.
[65]  Barker, F.G., 2nd; Davis, R.L.; Chang, S.M.; Prados, M.D. Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 1996, 77, 1161–1166, doi:10.1002/(SICI)1097-0142(19960315)77:6<1161::AID-CNCR24>3.0.CO;2-Z.
[66]  Brat, D.J.; Kaur, B.; van Meir, E.G. Genetic modulation of hypoxia induced gene expression and angiogenesis: Relevance to brain tumors. Front. Biosci. 2003, 8, d100–d116, doi:10.2741/942.
[67]  Burger, P.C.; Vollmer, R.T. Histologic factors of prognostic significance in the glioblastoma multiforme. Cancer 1980, 46, 1179–1186, doi:10.1002/1097-0142(19800901)46:5<1179::AID-CNCR2820460517>3.0.CO;2-0.
[68]  Evans, S.M.; Judy, K.D.; Dunphy, I.; Jenkins, W.T.; Nelson, P.T.; Collins, R.; Wileyto, E.P.; Jenkins, K.; Hahn, S.M.; Stevens, C.W.; et al. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res. 2004, 64, 1886–1892.
[69]  Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 1995, 92, 5510–5514, doi:10.1073/pnas.92.12.5510.
[70]  Kim, J.W.; Gao, P.; Dang, C.V. Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev. 2007, 26, 291–298, doi:10.1007/s10555-007-9060-4.
[71]  Semenza, G.L. HIF-1: Upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 2010, 20, 51–56, doi:10.1016/j.gde.2009.10.009.
[72]  Denko, N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 2008, 8, 705–713, doi:10.1038/nrc2468.
[73]  Carro, M.S.; Lim, W.K.; Alvarez, M.J.; Bollo, R.J.; Zhao, X.; Snyder, E.Y.; Sulman, E.P.; Anne, S.L.; Doetsch, F.; Colman, H.; et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010, 463, 318–325.
[74]  Maslov, S.; Sneppen, K. Specificity and stability in topology of protein networks. Science 2002, 296, 910–913, doi:10.1126/science.1065103.
[75]  Kim, J.; Chu, J.; Shen, X.; Wang, J.; Orkin, S.H. An extended transcriptional network for pluripotency of embryonic stem cells. Cell 2008, 132, 1049–1061.
[76]  Orkin, S.H.; Wang, J.; Kim, J.; Chu, J.; Rao, S.; Theunissen, T.W.; Shen, X.; Levasseur, D.N. The transcriptional network controlling pluripotency in ES cells. Cold Spring Harb. Symp. Quant. Biol. 2008, 73, 195–202, doi:10.1101/sqb.2008.72.001.
[77]  Sumazin, P.; Yang, X.; Chiu, H.S.; Chung, W.J.; Iyer, A.; Llobet-Navas, D.; Rajbhandari, P.; Bansal, M.; Guarnieri, P.; Silva, J.; et al. An extensive microrna-mediated network of rna-rna interactions regulates established oncogenic pathways in glioblastoma. Cell 2011, 147, 370–381.
[78]  Xiao, F.; Zuo, Z.; Cai, G.; Kang, S.; Gao, X.; Li, T. Mirecords: An integrated resource for microrna-target interactions. Nucleic Acids Res. 2009, 37, D105–D110, doi:10.1093/nar/gkn851.
[79]  Cai, X.; Hagedorn, C.H.; Cullen, B.R. Human micrornas are processed from capped, polyadenylated transcripts that can also function as mrnas. RNA 2004, 10, 1957–1966, doi:10.1261/rna.7135204.
[80]  Lee, Y.; Kim, M.; Han, J.; Yeom, K.H.; Lee, S.; Baek, S.H.; Kim, V.N. MicroRNA genes are transcribed by rna polymerase II. EMBO J. 2004, 23, 4051–4060.
[81]  Seitz, H.; Youngson, N.; Lin, S.P.; Dalbert, S.; Paulsen, M.; Bachellerie, J.P.; Ferguson-Smith, A.C.; Cavaille, J. Imprinted microrna genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nat. Genet. 2003, 34, 261–262.
[82]  Lee, Y.; Jeon, K.; Lee, J.T.; Kim, S.; Kim, V.N. MicroRNA maturation: Stepwise processing and subcellular localization. EMBO J. 2002, 21, 4663–4670, doi:10.1093/emboj/cdf476.
[83]  Okamura, K.; Hagen, J.W.; Duan, H.; Tyler, D.M.; Lai, E.C. The mirtron pathway generates microrna-class regulatory RNAs in drosophila. Cell 2007, 130, 89–100.
[84]  Ruby, J.G.; Jan, C.H.; Bartel, D.P. Intronic microRNA precursors that bypass Drosha processing. Nature 2007, 448, 83–86.
[85]  Bohnsack, M.T.; Czaplinski, K.; Gorlich, D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 2004, 10, 185–191.
[86]  Lund, E.; Guttinger, S.; Calado, A.; Dahlberg, J.E.; Kutay, U. Nuclear export of microRNA precursors. Science 2004, 303, 95–98.
[87]  Yi, R.; Qin, Y.; Macara, I.G.; Cullen, B.R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003, 17, 3011–3016, doi:10.1101/gad.1158803.
[88]  Zhang, H.; Kolb, F.A.; Jaskiewicz, L.; Westhof, E.; Filipowicz, W. Single processing center models for human Dicer and bacterial RNase III. Cell 2004, 118, 57–68, doi:10.1016/j.cell.2004.06.017.
[89]  Mourelatos, Z.; Dostie, J.; Paushkin, S.; Sharma, A.; Charroux, B.; Abel, L.; Rappsilber, J.; Mann, M.; Dreyfuss, G. Mirnps: A novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 2002, 16, 720–728, doi:10.1101/gad.974702.
[90]  Liu, J.; Carmell, M.A.; Rivas, F.V.; Marsden, C.G.; Thomson, J.M.; Song, J.J.; Hammond, S.M.; Joshua-Tor, L.; Hannon, G.J. Argonaute2 is the catalytic engine of mammalian RNAi. Science 2004, 305, 1437–1441.
[91]  Meister, G.; Landthaler, M.; Patkaniowska, A.; Dorsett, Y.; Teng, G.; Tuschl, T. Human argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 2004, 15, 185–197, doi:10.1016/j.molcel.2004.07.007.
[92]  Pillai, R.S.; Artus, C.G.; Filipowicz, W. Tethering of human ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA 2004, 10, 1518–1525.
[93]  Brennecke, J.; Stark, A.; Russell, R.B.; Cohen, S.M. Principles of microRNA-target recognition. PLoS Biol. 2005, 3, e85.
[94]  Doench, J.G.; Sharp, P.A. Specificity of microRNA target selection in translational repression. Genes Dev. 2004, 18, 504–511, doi:10.1101/gad.1184404.
[95]  Grimson, A.; Farh, K.K.; Johnston, W.K.; Garrett-Engele, P.; Lim, L.P.; Bartel, D.P. MicroRNA targeting specificity in mammals: Determinants beyond seed pairing. Mol. Cell 2007, 27, 91–105.
[96]  Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120, 15–20, doi:10.1016/j.cell.2004.12.035.
[97]  Nielsen, C.B.; Shomron, N.; Sandberg, R.; Hornstein, E.; Kitzman, J.; Burge, C.B. Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 2007, 13, 1894–1910.
[98]  Rana, T.M. Illuminating the silence: Understanding the structure and function of small RNAs. Nat. Rev. Mol. Cell Biol. 2007, 8, 23–36, doi:10.1038/nrm2085.
[99]  Zhang, Y.; Dutta, A.; Abounader, R. The role of microRNAs in glioma initiation and progression. Front. Biosci. 2012, 17, 700–712, doi:10.2741/3952.
[100]  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, 1636–1644, doi:10.1111/j.1582-4934.2011.01317.x.
[101]  Chen, L.; Zhang, J.; Han, L.; Zhang, A.; Zhang, C.; Zheng, Y.; Jiang, T.; Pu, P.; Jiang, C.; Kang, C. Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status. Oncol. Rep. 2012, 27, 854–860.
[102]  Quintavalle, C.; Garofalo, M.; Zanca, C.; Romano, G.; Iaboni, M.; del Basso de Caro, M.; Martinez-Montero, J.C.; Incoronato, M.; Nuovo, G.; Croce, C.M.; et al. MiR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate ptpmu. Oncogene 2012, 31, 858–868.
[103]  Hsu, S.D.; Lin, F.M.; Wu, W.Y.; Liang, C.; Huang, W.C.; Chan, W.L.; Tsai, W.T.; Chen, G.Z.; Lee, C.J.; Chiu, C.M.; et al. Mirtarbase: A database curates experimentally validated microRNA-target interactions. Nucleic Acids Res. 2011, 39, D163–D169.
[104]  Huang da, W.; Sherman, B.T.; Lempicki, R.A. Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009, 37, 1–13.
[105]  Dong, H.; Luo, L.; Hong, S.; Siu, H.; Xiao, Y.; Jin, L.; Chen, R.; Xiong, M. Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma. BMC Syst. Biol. 2010, 4, 163, doi:10.1186/1752-0509-4-163.
[106]  Gal, H.; Pandi, G.; Kanner, A.A.; Ram, Z.; Lithwick-Yanai, G.; Amariglio, N.; Rechavi, G.; Givol, D. MiR-451 and imatinib mesylate inhibit tumor growth of glioblastoma stem cells. Biochem. Biophys. Res. Commun. 2008, 376, 86–90.
[107]  Godlewski, J.; Newton, H.B.; Chiocca, E.A.; Lawler, S.E. MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ. 2010, 17, 221–228, doi:10.1038/cdd.2009.71.
[108]  Kefas, B.; Godlewski, J.; Comeau, L.; Li, Y.; Abounader, R.; Hawkinson, M.; Lee, J.; Fine, H.; Chiocca, E.A.; Lawler, S.; et al. MicroRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 2008, 68, 3566–3572.
[109]  Silber, J.; Lim, D.A.; Petritsch, C.; Persson, A.I.; Maunakea, A.K.; Yu, M.; Vandenberg, S.R.; Ginzinger, D.G.; James, C.D.; Costello, J.F.; et al. MiR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6, 14, doi:10.1186/1741-7015-6-14.
[110]  Zhang, Y.; Chao, T.; Li, R.; Liu, W.; Chen, Y.; Yan, X.; Gong, Y.; Yin, B.; Qiang, B.; Zhao, J.; et al. MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J. Mol. Med. 2009, 87, 43–51, doi:10.1007/s00109-008-0403-6.
[111]  Fan, X.; Khaki, L.; Zhu, T.S.; Soules, M.E.; Talsma, C.E.; Gul, N.; Koh, C.; Zhang, J.; Li, Y.M.; Maciaczyk, J.; et al. Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010, 28, 5–16.
[112]  Li, Y.; Guessous, F.; Zhang, Y.; Dipierro, C.; Kefas, B.; Johnson, E.; Marcinkiewicz, L.; Jiang, J.; Yang, Y.; Schmittgen, T.D.; et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009, 69, 7569–7576.
[113]  Kefas, B.; Comeau, L.; Floyd, D.H.; Seleverstov, O.; Godlewski, J.; Schmittgen, T.; Jiang, J.; diPierro, C.G.; Li, Y.; Chiocca, E.A.; et al. The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J. Neurosci. 2009, 29, 15161–15168.
[114]  Chen, Y.; Gorski, D.H. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes gax and hoxa5. Blood 2008, 111, 1217–1226.
[115]  Dews, M.; Homayouni, A.; Yu, D.; Murphy, D.; Sevignani, C.; Wentzel, E.; Furth, E.E.; Lee, W.M.; Enders, G.H.; Mendell, J.T.; et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat. Genet. 2006, 38, 1060–1065.
[116]  Fasanaro, P.; D’Alessandra, Y.; di Stefano, V.; Melchionna, R.; Romani, S.; Pompilio, G.; Capogrossi, M.C.; Martelli, F. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 2008, 283, 15878–15883.
[117]  Fish, J.E.; Santoro, M.M.; Morton, S.U.; Yu, S.; Yeh, R.F.; Wythe, J.D.; Ivey, K.N.; Bruneau, B.G.; Stainier, D.Y.; Srivastava, D. miR-126 Regulates angiogenic signaling and vascular integrity. Dev. Cell 2008, 15, 272–284.
[118]  Hua, Z.; Lv, Q.; Ye, W.; Wong, C.K.; Cai, G.; Gu, D.; Ji, Y.; Zhao, C.; Wang, J.; Yang, B.B.; et al. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 2006, 1, e116.
[119]  Kuehbacher, A.; Urbich, C.; Zeiher, A.M.; Dimmeler, S. Role of dicer and drosha for endothelial microRNA expression and angiogenesis. Circ. Res. 2007, 101, 59–68, doi:10.1161/CIRCRESAHA.107.153916.
[120]  Kuhnert, F.; Mancuso, M.R.; Hampton, J.; Stankunas, K.; Asano, T.; Chen, C.Z.; Kuo, C.J. Attribution of vascular phenotypes of the murine EGFL7 locus to the microRNA miR-126. Development 2008, 135, 3989–3993, doi:10.1242/dev.029736.
[121]  Lee, D.Y.; Deng, Z.; Wang, C.H.; Yang, B.B. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc. Natl. Acad. Sci. USA 2007, 104, 20350–20355, doi:10.1073/pnas.0706901104.
[122]  Pulkkinen, K.; Malm, T.; Turunen, M.; Koistinaho, J.; Yla-Herttuala, S. Hypoxia induces microRNA miR-210 in vitro and in vivo Ephrin-a3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Lett. 2008, 582, 2397–2401.
[123]  Wang, S.; Aurora, A.B.; Johnson, B.A.; Qi, X.; McAnally, J.; Hill, J.A.; Richardson, J.A.; Bassel-Duby, R.; Olson, E.N. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 2008, 15, 261–271, doi:10.1016/j.devcel.2008.07.002.
[124]  Wurdinger, T.; Tannous, B.A.; Saydam, O.; Skog, J.; Grau, S.; Soutschek, J.; Weissleder, R.; Breakefield, X.O.; Krichevsky, A.M. miR-296 Regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 2008, 14, 382–393, doi:10.1016/j.ccr.2008.10.005.
[125]  Smits, M.; Wurdinger, T.; van Het Hof, B.; Drexhage, J.A.; Geerts, D.; Wesseling, P.; Noske, D.P.; Vandertop, W.P.; de Vries, H.E.; Reijerkerk, A. Myc-associated zinc finger protein (MAZ) is regulated by miR-125b and mediates VEGF-induced angiogenesis in glioblastoma. FASEB J. 2012.
[126]  Smits, M.; Mir, S.E.; Nilsson, R.J.; van der Stoop, P.M.; Niers, J.M.; Marquez, V.E.; Cloos, J.; Breakefield, X.O.; Krichevsky, A.M.; Noske, D.P.; et al. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS One 2011, 6, e16282.
[127]  Poliseno, L.; Tuccoli, A.; Mariani, L.; Evangelista, M.; Citti, L.; Woods, K.; Mercatanti, A.; Hammond, S.; Rainaldi, G. MicroRNAs modulate the angiogenic properties of huvecs. Blood 2006, 108, 3068–3071, doi:10.1182/blood-2006-01-012369.
[128]  Wang, X.H.; Qian, R.Z.; Zhang, W.; Chen, S.F.; Jin, H.M.; Hu, R.M. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin. Exp. Pharmacol. Physiol. 2009, 36, 181–188, doi:10.1111/j.1440-1681.2008.05057.x.
[129]  Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Nuovo, G.; Palatini, J.; de Lay, M.; van Brocklyn, J.; Ostrowski, M.C.; Chiocca, E.A.; Lawler, S.E. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol. Cell 2010, 37, 620–632, doi:10.1016/j.molcel.2010.02.018.
[130]  Gao, P.; Tchernyshyov, I.; Chang, T.C.; Lee, Y.S.; Kita, K.; Ochi, T.; Zeller, K.I.; de Marzo, A.M.; van Eyk, J.E.; Mendell, J.T.; et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009, 458, 762–765.
[131]  Olive, V.; Bennett, M.J.; Walker, J.C.; Ma, C.; Jiang, I.; Cordon-Cardo, C.; Li, Q.J.; Lowe, S.W.; Hannon, G.J.; He, L. miR-19 Is a key oncogenic component of miR-17-92. Genes Dev. 2009, 23, 2839–2849.
[132]  Kulshreshtha, R.; Ferracin, M.; Negrini, M.; Calin, G.A.; Davuluri, R.V.; Ivan, M. Regulation of microRNA expression: The hypoxic component. Cell Cycle 2007, 6, 1426–1431.
[133]  Chan, S.Y.; Zhang, Y.Y.; Hemann, C.; Mahoney, C.E.; Zweier, J.L.; Loscalzo, J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009, 10, 273–284, doi:10.1016/j.cmet.2009.08.015.
[134]  Cascio, S.; D’Andrea, A.; Ferla, R.; Surmacz, E.; Gulotta, E.; Amodeo, V.; Bazan, V.; Gebbia, N.; Russo, A. miR-20b Modulates VEGF expression by targeting HIF-1α and STAT3 in MCF-7 breast cancer cells. J. Cell. Physiol. 2010, 224, 242–249.
[135]  Rane, S.; He, M.; Sayed, D.; Vashistha, H.; Malhotra, A.; Sadoshima, J.; Vatner, D.E.; Vatner, S.F.; Abdellatif, M. Downregulation of miR-199a derepresses hypoxia-inducible factor-1α and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ. Res. 2009, 104, 879–886, doi:10.1161/CIRCRESAHA.108.193102.
[136]  Stiles, C.D.; Rowitch, D.H. Glioma stem cells: A midterm exam. Neuron 2008, 58, 832–846, doi:10.1016/j.neuron.2008.05.031.
[137]  Shi, L.; Zhang, J.; Pan, T.; Zhou, J.; Gong, W.; Liu, N.; Fu, Z.; You, Y. MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Res. 2010, 1312, 120–126.
[138]  Bruggeman, S.W.; Hulsman, D.; Tanger, E.; Buckle, T.; Blom, M.; Zevenhoven, J.; van Tellingen, O.; van Lohuizen, M. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007, 12, 328–341.
[139]  Dirks, P. Bmi1 and cell of origin determinants of brain tumor phenotype. Cancer Cell 2007, 12, 295–297, doi:10.1016/j.ccr.2007.10.003.
[140]  Jin, X.; Yin, J.; Kim, S.H.; Sohn, Y.W.; Beck, S.; Lim, Y.C.; Nam, D.H.; Choi, Y.J.; Kim, H. EGFR-AKT-SMAD signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res. 2011, 71, 7125–7134, doi:10.1158/0008-5472.CAN-11-1330.
[141]  Piccirillo, S.G.; Reynolds, B.A.; Zanetti, N.; Lamorte, G.; Binda, E.; Broggi, G.; Brem, H.; Olivi, A.; Dimeco, F.; Vescovi, A.L. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006, 444, 761–765.
[142]  Shih, A.H.; Holland, E.C. Notch signaling enhances nestin expression in gliomas. Neoplasia 2006, 8, 1072–1082.
[143]  Wang, J.; Wakeman, T.P.; Lathia, J.D.; Hjelmeland, A.B.; Wang, X.F.; White, R.R.; Rich, J.N.; Sullenger, B.A. Notch promotes radioresistance of glioma stem cells. Stem Cells 2010, 28, 17–28.
[144]  Zhang, X.P.; Zheng, G.; Zou, L.; Liu, H.L.; Hou, L.H.; Zhou, P.; Yin, D.D.; Zheng, Q.J.; Liang, L.; Zhang, S.Z.; et al. Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells. Mol. Cell. Biochem. 2008, 307, 101–108.
[145]  Cao, Y.; Nagesh, V.; Hamstra, D.; Tsien, C.I.; Ross, B.D.; Chenevert, T.L.; Junck, L.; Lawrence, T.S. The extent and severity of vascular leakage as evidence of tumor aggressiveness in high-grade gliomas. Cancer Res. 2006, 66, 8912–8917.
[146]  Rutten, E.H.; Doesburg, W.H.; Slooff, J.L. Histologic factors in the grading and prognosis of astrocytoma grade I-IV. J. Neurooncol. 1992, 13, 223–230.
[147]  Wang, S.; Olson, E.N. Angiomirs—Key regulators of angiogenesis. Curr. Opin. Genet. Dev. 2009, 19, 205–211, doi:10.1016/j.gde.2009.04.002.
[148]  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. Neurooncology 2010, 12, 1102–1112.
[149]  Chan, J.A.; Krichevsky, A.M.; Kosik, K.S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005, 65, 6029–6033, doi:10.1158/0008-5472.CAN-05-0137.
[150]  Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Williams, S.; Otsuki, A.; Nuovo, G.; Raychaudhury, A.; Newton, H.B.; Chiocca, E.A.; Lawler, S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008, 68, 9125–9130.
[151]  Huse, J.T.; Brennan, C.; Hambardzumyan, D.; Wee, B.; Pena, J.; Rouhanifard, S.H.; Sohn-Lee, C.; le Sage, C.; Agami, R.; Tuschl, T.; et al. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009, 23, 1327–1337, doi:10.1101/gad.1777409.
[152]  Nan, Y.; Han, L.; Zhang, A.; Wang, G.; Jia, Z.; Yang, Y.; Yue, X.; Pu, P.; Zhong, Y.; Kang, C. MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res. 2010, 1359, 14–21, doi:10.1016/j.brainres.2010.08.074.
[153]  Wang, Y.; Wang, X.; Zhang, J.; Sun, G.; Luo, H.; Kang, C.; Pu, P.; Jiang, T.; Liu, N.; You, Y. MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas. J. Neurooncol. 2012, 106, 217–224, doi:10.1007/s11060-011-0679-1.
[154]  Zhang, J.; Han, L.; Ge, Y.; Zhou, X.; Zhang, A.; Zhang, C.; Zhong, Y.; You, Y.; Pu, P.; Kang, C. miR-221/222 Promote malignant progression of glioma through activation of the Akt pathway. Int. J. Oncol. 2010, 36, 913–920.
[155]  Zhou, X.; Ren, Y.; Moore, L.; Mei, M.; You, Y.; Xu, P.; Wang, B.; Wang, G.; Jia, Z.; Pu, P.; et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of pten status. Lab. Invest. 2010, 90, 144–155, doi:10.1038/labinvest.2009.126.
[156]  Papagiannakopoulos, T.; Shapiro, A.; Kosik, K.S. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008, 68, 8164–8172, doi:10.1158/0008-5472.CAN-08-1305.
[157]  Suh, S.S.; Yoo, J.Y.; Nuovo, G.J.; Jeon, Y.J.; Kim, S.; Lee, T.J.; Kim, T.; Bakacs, A.; Alder, H.; Kaur, B.; et al. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. Proc. Natl. Acad. Sci. USA 2012, 109, 5316–5321.
[158]  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, doi:10.1016/j.arcmed.2010.02.007.
[159]  Jiang, S.; Zhang, L.F.; Zhang, H.W.; Hu, S.; Lu, M.H.; Liang, S.; Li, B.; Li, Y.; Li, D.; Wang, E.D.; et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J. 2012, 31, 1985–1998, doi:10.1038/emboj.2012.45.
[160]  Wolf, A.; Agnihotri, S.; Munoz, D.; Guha, A. Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme. Neurobiol. Dis. 2011, 44, 84–91, doi:10.1016/j.nbd.2011.06.007.
[161]  O’Donnell, K.A.; Wentzel, E.A.; Zeller, K.I.; Dang, C.V.; Mendell, J.T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005, 435, 839–843.
[162]  Chan, S.Y.; Loscalzo, J. MicroRNA-210: A unique and pleiotropic hypoxamir. Cell Cycle 2010, 9, 1072–1083, doi:10.4161/cc.9.6.11006.
[163]  Lages, E.; Guttin, A.; El Atifi, M.; Ramus, C.; Ipas, H.; Dupre, I.; Rolland, D.; Salon, C.; Godfraind, C.; deFraipont, F.; et al. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. PLoS One 2011, 6, e20600.
[164]  Poliseno, L.; Salmena, L.; Zhang, J.; Carver, B.; Haveman, W.J.; Pandolfi, P.P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010, 465, 1033–1038.
[165]  Salmena, L.; Poliseno, L.; Tay, Y.; Kats, L.; Pandolfi, P.P. A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell 2011, 146, 353–358, doi:10.1016/j.cell.2011.07.014.
[166]  Sumazin, P.; Yang, X.; Chiu, H.S.; Chung, W.J.; Iyer, A.; Llobet-Navas, D.; Rajbhandari, P.; Bansal, M.; Guarnieri, P.; Silva, J.; et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 2011, 147, 370–381.
[167]  Tay, Y.; Kats, L.; Salmena, L.; Weiss, D.; Tan, S.M.; Ala, U.; Karreth, F.; Poliseno, L.; Provero, P.; di Cunto, F.; et al. Coding-independent regulation of the tumor suppressor pten by competing endogenous mRNAs. Cell 2011, 147, 344–357.

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