Molecular Biology Reports

, Volume 40, Issue 4, pp 2789–2798 | Cite as

MicroRNA-153 is tumor suppressive in glioblastoma stem cells

  • Shiguang ZhaoEmail author
  • Yifan Deng
  • Yaohua Liu
  • Xin Chen
  • Guang Yang
  • Yulong Mu
  • Daming Zhang
  • Jianhao Kang
  • Zhaoli Wu


Glioblastoma multiforme (GBM) is lethal brain tumor thought to arise from GBM stem cells (GBM-SCs). MicroRNAs carry out post-transcriptional regulation of various cellular processes that modulate the stemness properties of GBM-SCs. Here, we investigated the critical role of miR-153 in GBM-SCs. First, GBM-SCs were isolated from six GBM specimens. These GBM-SCs formed GBM spheres, expressed markers associated with neural stem cells, and possessed the capacity for self-renewal and multilineage differentiation. Then qRT-PCR analysis showed that miR-153 expression was down-regulated in GBM tissues relative to normal brain tissues, and in CD133 positive cells relative to CD133 negative cells. This project demonstrates for the first time that transient transfection of miR-153 into GBM-SCs can inhibit their stemness properties, such as impairing self-renewal ability and inducing differentiation. Meanwhile, miR-153 can also repress GBM-SCs growth and induce apoptosis. Altogether, these results indicate that reactivation of miR-153 expression suggests novel therapeutic strategies for GBM-SCs.


Glioblastoma multiforme Glioblastoma stem cells MiR-153 Self-renewal ability Differentiation 



This study was supported by National Natural Science Foundations of China (Nos. 30901533, 81172388, 30973078).

Conflict of interest

The authors declare no conflict of interests.


  1. 1.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. doi: 10.1056/NEJMra0708126 PubMedCrossRefGoogle Scholar
  2. 2.
    Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768. doi: 10.1038/nrc2499 PubMedCrossRefGoogle Scholar
  3. 3.
    Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med 17(3):313–319. doi: 10.1038/nm.2304 PubMedCrossRefGoogle Scholar
  4. 4.
    Takebe N, Harris PJ, Warren RQ, Ivy SP (2010) Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. doi: 10.1038/nrclinonc.2010.196 Google Scholar
  5. 5.
    Singh S, Clarke I, Terasaki M, Bonn V, Hawkins C, Squire J, Dirks P (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828PubMedGoogle Scholar
  6. 6.
    Yuan X, Curtin J, Xiong Y, Liu G, Black K, Yu J (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392–9400PubMedCrossRefGoogle Scholar
  7. 7.
    Bleau A, Hambardzumyan D, Ozawa T, Fomchenko E, Huse JT, Brennan C, Holland E (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4(3):226–235PubMedCrossRefGoogle Scholar
  8. 8.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760. doi: 10.1038/nature05236 PubMedCrossRefGoogle Scholar
  9. 9.
    Siebzehnrubl FA, Reynolds BA, Vescovi A, Steindler DA, Deleyrolle LP (2011) The origins of glioma: E pluribus unum? Glia 59(8):1135–1147. doi: 10.1002/glia.21143 PubMedCrossRefGoogle Scholar
  10. 10.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–269. doi: 10.1038/nrc1840 PubMedCrossRefGoogle Scholar
  11. 11.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838. doi: 10.1038/nature03702 PubMedCrossRefGoogle Scholar
  12. 12.
    Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR, Israel MA (2007) Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67(6):2456–2468. doi: 10.1158/0008-5472.CAN-06-2698 PubMedCrossRefGoogle Scholar
  13. 13.
    Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68(19):8164–8172. doi: 10.1158/0008-5472.CAN-08-1305 PubMedCrossRefGoogle Scholar
  14. 14.
    Huse JT, Brennan C, Hambardzumyan D, Wee B, Holland EC (2009) The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev 23(11):1327–1337PubMedCrossRefGoogle Scholar
  15. 15.
    Gabriely G, Yi M, Narayan RS, Niers JM, Wurdinger T, Imitola J, Ligon KL, Kesari S, Esau C, Stephens RM, Tannous BA, Krichevsky AM (2011) Human glioma growth is controlled by microRNA-10b. Cancer Res 71(10):3563–3572. doi: 10.1158/0008-5472.CAN-10-3568 PubMedCrossRefGoogle Scholar
  16. 16.
    Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, JOhnson E (2009) MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 69(19):7569–7576PubMedCrossRefGoogle Scholar
  17. 17.
    Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14. doi: 10.1186/1741-7015-6-14 PubMedCrossRefGoogle Scholar
  18. 18.
    Godlewski J, Newton H, Chiocca E, Lawler S (2009) MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ 17(2):221–228PubMedCrossRefGoogle Scholar
  19. 19.
    Doxakis E (2010) Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem 285(17):12726–12734. doi: 10.1074/jbc.M109.086827 PubMedCrossRefGoogle Scholar
  20. 20.
    Liang C, Zhu H, Xu Y, Huang L, Ma C, Deng W, Liu Y, Qin C (2012) MicroRNA-153 negatively regulates the expression of amyloid precursor protein and amyloid precursor-like protein 2. Brain Res 1455:103–113. doi: 10.1016/j.brainres.2011.10.051 PubMedCrossRefGoogle Scholar
  21. 21.
    Xu J, Liao X, Wong C (2010) Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int J Cancer 126(4):1029–1035. doi: 10.1002/ijc.24823 PubMedGoogle Scholar
  22. 22.
    Pollard S, Yashikawa K, Clarke I, Danovi D, Stricker S, Russell R, Bayani J (2009) Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4(6):568–580PubMedCrossRefGoogle Scholar
  23. 23.
    Cheng J, Liu B, Zhang X (2009) How powerful is CD133 as a cancer stem cell marker in brain tumors. Cancer Treat Rev 35(5):403–408PubMedCrossRefGoogle Scholar
  24. 24.
    Venere M, Fine HA, Dirks PB, Rich JN (2011) Cancer stem cells in gliomas: identifying and understanding the apex cell in cancer’s hierarchy. Glia 59(8):1148–1154. doi: 10.1002/glia.21185 PubMedCrossRefGoogle Scholar
  25. 25.
    Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353(8):811–822. doi: 10.1056/NEJMra043666 PubMedCrossRefGoogle Scholar
  26. 26.
    Stiles C, Rowitch D (2008) Glioma stem cells: a midterm exam. Neuron 58(6):832–846PubMedCrossRefGoogle Scholar
  27. 27.
    Angers S, Moon RT (2009) Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 10(7):468–477. doi: 10.1038/nrm2717 PubMedGoogle Scholar
  28. 28.
    Yue X, Lan F, Yang W, Yang Y, Han L, Zhang A, Liu J, Zeng H, Jiang T, Pu P, Kang C (2010) Interruption of beta-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells. Brain Res 1366:27–37. doi: 10.1016/j.brainres.2010.10.032 PubMedCrossRefGoogle Scholar
  29. 29.
    Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD, Nusse R (2008) Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci USA 105(44):16970–16975. doi: 10.1073/pnas.0808616105 PubMedCrossRefGoogle Scholar
  30. 30.
    Gao C, Chen YG (2010) Dishevelled: the hub of Wnt signaling. Cell Signal 22(5):717–727. doi: 10.1016/j.cellsig.2009.11.021 PubMedCrossRefGoogle Scholar
  31. 31.
    Pulvirenti T, Van Der Heijden M, Droms LA, Huse JT, Tabar V, Hall A (2011) Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas. Cancer Res 71(23):7280–7290. doi: 10.1158/0008-5472.CAN-11-1531 PubMedCrossRefGoogle Scholar
  32. 32.
    Sareddy GR, Panigrahi M, Challa S, Mahadevan A, Babu PP (2009) Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int 55(5):307–317. doi: 10.1016/j.neuint.2009.03.016 PubMedCrossRefGoogle Scholar
  33. 33.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. doi: 10.1016/j.cell.2009.01.002 PubMedCrossRefGoogle Scholar
  34. 34.
    Kasinski AL, Slack FJ (2011) Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 11(12):849–864. doi: 10.1038/nrc3166 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Shiguang Zhao
    • 1
    • 2
    Email author
  • Yifan Deng
    • 1
    • 2
  • Yaohua Liu
    • 1
    • 2
  • Xin Chen
    • 1
    • 2
  • Guang Yang
    • 1
    • 2
  • Yulong Mu
    • 1
    • 2
  • Daming Zhang
    • 1
    • 2
  • Jianhao Kang
    • 1
    • 2
  • Zhaoli Wu
    • 1
    • 2
  1. 1.Department of NeurosurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinPeople’s Republic of China
  2. 2.Institute of Brain ScienceHarbin Medical UniversityHarbinPeople’s Republic of China

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