Journal of Neuro-Oncology

, Volume 112, Issue 2, pp 153–163 | Cite as

Oncogenic effects of miR-10b in glioblastoma stem cells

  • Fadila Guessous
  • Melissa Alvarado-Velez
  • Lukasz Marcinkiewicz
  • Ying Zhang
  • Jungeun Kim
  • Simon Heister
  • Benjamin Kefas
  • Jakub Godlewski
  • David Schiff
  • Benjamin Purow
  • Roger AbounaderEmail author
Laboratory Investigation


MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.


MicroRNA-10b Glioblastoma Glioblastoma stem cells Migration Invasion 



Supported by NIH RO1 NS045209 (R. Abounader) and NIH R01 CA134843 (R. Abounader).

Conflict of interest

None of the authors has any conflict of interest associated with the present work.


  1. 1.
    Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710PubMedCrossRefGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  3. 3.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  4. 4.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021PubMedCrossRefGoogle Scholar
  5. 5.
    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403PubMedCrossRefGoogle Scholar
  6. 6.
    Hadjipanayis CG, Van Meir EG (2009) Brain cancer propagating cells: biology, genetics and targeted therapies. Trends Mol Med 15:519–530PubMedCrossRefGoogle Scholar
  7. 7.
    Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S (2010) Cancer stem cells in glioblastoma–molecular signaling and therapeutic targeting. Protein Cell 1:638–655PubMedCrossRefGoogle Scholar
  8. 8.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRefGoogle Scholar
  9. 9.
    Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA (2009) MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer 9:293–302PubMedCrossRefGoogle Scholar
  10. 10.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet 9:102–114PubMedCrossRefGoogle Scholar
  11. 11.
    Godlewski J, Newton HB, Chiocca EA, Lawler SE (2010) MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ 17:221–228PubMedCrossRefGoogle Scholar
  12. 12.
    Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R (2009) MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 69:7569–7576PubMedCrossRefGoogle Scholar
  13. 13.
    Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R (2010) MicroRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 9:1031–1036PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang Y, Dutta A, Abounader R (2012) The role of microRNAs in glioma initiation and progression. Front Biosci 17:700–712PubMedCrossRefGoogle Scholar
  15. 15.
    Baffa R, Fassan M, Volinia S, O’Hara B, Liu CG, Palazzo JP, Gardiman M, Rugge M, Gomella LG, Croce CM, Rosenberg A (2009) MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol 219:214–221PubMedCrossRefGoogle Scholar
  16. 16.
    Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–688PubMedCrossRefGoogle Scholar
  17. 17.
    Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908PubMedCrossRefGoogle Scholar
  18. 18.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334:1351–1358PubMedCrossRefGoogle Scholar
  19. 19.
    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 71:3563–3572PubMedCrossRefGoogle Scholar
  20. 20.
    Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E (2009) MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 125:1407–1413PubMedCrossRefGoogle Scholar
  21. 21.
    Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689PubMedCrossRefGoogle Scholar
  22. 22.
    Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3:87–98PubMedCrossRefGoogle Scholar
  23. 23.
    Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–899PubMedCrossRefGoogle Scholar
  24. 24.
    Jin H, Yu Y, Chrisler WB, Xiong Y, Hu D, Lei C (2012) Delivery of microRNA-10b with polylysine nanoparticles for inhibition of breast cancer cell wound healing. Breast Cancer (Auckl) 6:9–19Google Scholar
  25. 25.
    Network CGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRefGoogle Scholar
  26. 26.
    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 444:756–760PubMedCrossRefGoogle Scholar
  27. 27.
    Rich JN, Bao S (2007) Chemotherapy and cancer stem cells. Cell Stem Cell 1:353–355PubMedCrossRefGoogle Scholar
  28. 28.
    Yang W, Wang C, Lin Y, Liu Q, Yu LX, Tang L, Yan HX, Fu J, Chen Y, Zhang HL, Tang L, Zheng LY, He YQ, Li YQ, Wu FQ, Zou SS, Li Z, Wu MC, Feng GS, Wang HY (2012) OV6(+) tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma. J Hepatol 57(3):613–620PubMedCrossRefGoogle Scholar
  29. 29.
    Lenz J, Karasek P, Jarkovsky J, Muckova K, Dite P, Kala Z, Veselska R, Hermanova M (2011) Clinicopathological correlations of nestin expression in surgically resectable pancreatic cancer including an analysis of perineural invasion. J Gastrointest Liver Dis 20:389–396Google Scholar
  30. 30.
    Siu A, Lee C, Dang D, Lee C, Ramos DM (2012) Stem cell markers as predictors of oral cancer invasion. Anticancer Res 32:1163–1166PubMedGoogle Scholar
  31. 31.
    Mohan A, Kandalam M, Ramkumar HL, Gopal L, Krishnakumar S (2006) Stem cell markers: ABCG2 and MCM2 expression in retinoblastoma. Br J Ophthalmol 90:889–893PubMedCrossRefGoogle Scholar
  32. 32.
    Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, Houvenaeghel G, Extra JM, Bertucci F, Jacquemier J, Xerri L, Dontu G, Stassi G, Xiao Y, Barsky SH, Birnbaum D, Viens P, Wicha MS (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16:45–55PubMedCrossRefGoogle Scholar
  33. 33.
    Lu YC, Chen YJ, Wang HM, Tsai CY, Chen WH, Huang YC, Fan KH, Tsai CN, Huang SF, Kang CJ, Chang JT, Cheng AJ (2012) Oncogenic function and early detection potential of miRNA-10b in oral cancer as identified by microRNA profiling. Cancer Prev Res (Phila) 5(4):665–674CrossRefGoogle Scholar
  34. 34.
    Chai G, Liu N, Ma J, Li H, Oblinger JL, Prahalad AK, Gong M, Chang LS, Wallace M, Muir D, Guha A, Phipps RJ, Hock JM, Yu X (2010) MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci 101:1997–2004. doi: 10.1111/j.1349-7006.2010.01616.x PubMedCrossRefGoogle Scholar
  35. 35.
    Tian Y, Luo A, Cai Y, Su Q, Ding F, Chen H, Liu Z (2010) MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J Biol Chem 285:7986–7994PubMedCrossRefGoogle Scholar
  36. 36.
    Bourguignon LY, Wong G, Earle C, Krueger K, Spevak CC (2010) Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion. J Biol Chem 285:36721–36735PubMedCrossRefGoogle Scholar
  37. 37.
    Ma L (2010) Role of miR-10b in breast cancer metastasis. Breast Cancer Res 12:210PubMedCrossRefGoogle Scholar
  38. 38.
    Liu Z, Zhu J, Cao H, Ren H, Fang X (2012) miR-10b promotes cell invasion through RhoC-AKT signaling pathway by targeting HOXD10 in gastric cancer. Int J Oncol 40(5):1553–1560PubMedGoogle Scholar
  39. 39.
    Moriarty CH, Pursell B, Mercurio AM (2010) miR-10b targets Tiam1: implications for Rac activation and carcinoma migration. J Biol Chem 285:20541–20546PubMedCrossRefGoogle Scholar
  40. 40.
    Gabriely G, Teplyuk NM, Krichevsky AM (2011) Context effect: microRNA-10b in cancer cell proliferation, spread and death. Autophagy 7:1384–1386PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Fadila Guessous
    • 1
  • Melissa Alvarado-Velez
    • 1
  • Lukasz Marcinkiewicz
    • 1
  • Ying Zhang
    • 1
  • Jungeun Kim
    • 1
  • Simon Heister
    • 1
  • Benjamin Kefas
    • 2
  • Jakub Godlewski
    • 3
  • David Schiff
    • 2
  • Benjamin Purow
    • 2
  • Roger Abounader
    • 1
    • 2
    Email author
  1. 1.Departments of Microbiology, Immunology and Cancer BiologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of NeurologyUniversity of VirginiaCharlottesvilleUSA
  3. 3.Laboratory for Neuro-oncology and NeurosciencesThe Ohio State UniversityColumbusUSA

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