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Let-7 microRNA inhibits the proliferation of human glioblastoma cells

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs comprising 21–23 nucleotides that regulate gene expression by transcriptionally repressing their complementary mRNAs. In particular, let-7 miRNA has been postulated to function as a tumor suppressor in various cancer cells, but not yet in glioblastoma. In this study, we investigated the anti-tumorigenic effect of let-7 miRNA in glioblastoma cells. Human glioblastoma cells (U251 or U87 cells) were transfected with let-7 miRNA and assayed for in-vitro proliferation, migration, and in-vivo tumor formation. Transfection of let-7 miRNA reduced expression of pan-RAS, N-RAS, and K-RAS in the glioblastoma cells. Let-7 miRNA also reduced the in-vitro proliferation and migration of the cells, and reduced the sizes of the tumors produced after transplantation into nude mice. However, let-7 miRNA exerted no effect on the proliferation of normal human astrocytes. These results indicate that let-7 miRNA has an anti-tumorigenic effect on glioblastoma cells, and suggest possible use of let-7 miRNA for treating glioblastoma.

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References

  1. Voelzke WR, Petty WJ, Lesser GJ (2008) Targeting the epidermal growth factor receptor in high-grade astrocytomas. Curr Treat Options Oncol 9:23–31

    Article  PubMed  Google Scholar 

  2. Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139

    Article  CAS  PubMed  Google Scholar 

  3. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    Article  CAS  PubMed  Google Scholar 

  4. Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647

    Article  CAS  PubMed  Google Scholar 

  5. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579

    Article  CAS  PubMed  Google Scholar 

  6. Reinhart BJ, Slack FJ, Basson M et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906

    Article  CAS  PubMed  Google Scholar 

  7. Takamizawa J, Konishi H, Yanagisawa K et al (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756

    Article  CAS  PubMed  Google Scholar 

  8. Akao Y, Nakagawa Y, Naoe T (2006) let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull 29:903–906

    Article  CAS  PubMed  Google Scholar 

  9. Schultz J, Lorenz P, Gross G et al (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 18:549–557

    Article  CAS  PubMed  Google Scholar 

  10. Yu F, Yao H, Zhu P et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123

    Article  CAS  PubMed  Google Scholar 

  11. Kumar MS, Erkeland SJ, Pester RE et al (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 105:3903–3908

    Article  CAS  PubMed  Google Scholar 

  12. Self AJ, Caron E, Paterson HF et al (2001) Analysis of R-Ras signalling pathways. J Cell Sci 114:1357–1366

    CAS  PubMed  Google Scholar 

  13. Nakada M, Niska JA, Tran NL et al (2005) EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. Am J Pathol 167:565–576

    Article  CAS  PubMed  Google Scholar 

  14. Perkins E, Calvert J, Lancon JA et al (2003) Inhibition of H-ras as a treatment for experimental brain C6 glioma. Brain Res Mol Brain Res 111:42–51

    Article  CAS  PubMed  Google Scholar 

  15. Goldberg L, Kloog Y (2006) A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res 66:11709–11717

    Article  CAS  PubMed  Google Scholar 

  16. Chu K, Jung KH, Kim SJ et al (2008) Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1alpha stabilization in the host brain. Brain Res 1207:182–192

    Article  CAS  PubMed  Google Scholar 

  17. Demuth T, Berens ME (2004) Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 70:217–228

    Article  PubMed  Google Scholar 

  18. Lawler S, Chiocca EA (2009) Emerging functions of microRNAs in glioblastoma. J Neurooncol 92:297–306

    Article  CAS  PubMed  Google Scholar 

  19. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65:6029–6033

    Article  CAS  PubMed  Google Scholar 

  20. Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68:8164–8172

    Article  CAS  PubMed  Google Scholar 

  21. Ciafre SA, Galardi S, Mangiola A et al (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334:1351–1358

    Article  CAS  PubMed  Google Scholar 

  22. Krichebsky AM, Gabriely G (2009) miR-21: a small multi-faceted RNA. J Cell Mol Med 13:39–53

    Article  Google Scholar 

  23. Gabriely G, Wurdinger T, Kesari S et al (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28:5369–5380

    Article  CAS  PubMed  Google Scholar 

  24. Conti A, Aguennouz M, La Torre D et al (2009) miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors. J Neurooncol 93:325–332

    Article  CAS  PubMed  Google Scholar 

  25. Li Y, Li W, Yang Y et al (2009) MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme. Brain Res 1286:13–18

    Article  CAS  PubMed  Google Scholar 

  26. Silber J, Lim DA, Petritsch C et al (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14

    Article  PubMed  Google Scholar 

  27. Godlewski J, Nowicki MO, Bronisz A et al (2008) Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68:9125–9130

    Article  CAS  PubMed  Google Scholar 

  28. Xia H, Qi Y, Ng SS et al (2009) microRNA-146b inhibits glioma cell migration and invasion by targeting MMPs. Brain Res 1269:158–165

    Article  CAS  PubMed  Google Scholar 

  29. Kefas B, Godlewski J, Comeau L et al (2008) microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 68:3566–3572

    Article  CAS  PubMed  Google Scholar 

  30. Shi L, Cheng Z, Zhang J et al (2008) hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res 1236:185–193

    Article  CAS  PubMed  Google Scholar 

  31. le Sage C, Nagel R, Egan DA et al (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26:3699–3708

    Article  PubMed  Google Scholar 

  32. Selbach M, Schwanhäusser B, Thierfelder N et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63

    Article  CAS  PubMed  Google Scholar 

  33. Ricarte-Filho JC, Fuziwara CS, Yamashita AS et al (2009) Effects of let-7 microRNA on cell growth and differentiation of papillary thyroid cancer. Transl Oncol 2:236–241

    PubMed  Google Scholar 

  34. Johnson CD, Esquela-Kerscher A, Stefani G et al (2007) The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 67:7713–7722

    Article  CAS  PubMed  Google Scholar 

  35. Zhou X, Ren Y, Moore L et al (2010) Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest 90:144–155

    Article  CAS  PubMed  Google Scholar 

  36. Sampson VB, Rong NH, Han J et al (2007) MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67:9762–9770

    Article  CAS  PubMed  Google Scholar 

  37. Christensen BC, Moyer BJ, Avissar M et al (2009) A let-7 microRNA-binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers. Carcinogenesis 30:1003–1007

    Article  CAS  PubMed  Google Scholar 

  38. Hummel R, Hussey DJ, Haier J et al (2010) MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer 46:298–311

    Article  CAS  PubMed  Google Scholar 

  39. Weidhaas JB, Babar I, Nallur SM et al (2007) MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 67:11111–11116

    Article  CAS  PubMed  Google Scholar 

  40. Legesse-Miller A, Elemento O, Pfau SJ et al (2009) let-7 overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34, and stabilization of Wee1 kinase in primary fibroblasts. J Biol Chem 284:6605–6609

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare (A092058), WCU-Neurocytomics program (800-20080848), FPR08K1301-02210, and SNUH grant (620071079), South Korea.

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Correspondence to Manho Kim.

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S.-T. Lee and K. Chu contributed equally to this work.

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Lee, ST., Chu, K., Oh, HJ. et al. Let-7 microRNA inhibits the proliferation of human glioblastoma cells. J Neurooncol 102, 19–24 (2011). https://doi.org/10.1007/s11060-010-0286-6

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  • DOI: https://doi.org/10.1007/s11060-010-0286-6

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