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Molecular and cellular biology
Sep, 2008;28 (17): 5369-80.

MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.

Galina Gabriely, Thomas Wurdinger, Santosh Kesari, Christine C Esau, Julja Burchard, Peter S Linsley, Anna M Krichevsky
Author Information
  1. Galina Gabriely: Center of Neurologic Diseases, Brigham and Women's Hospital, 4 Blackfan Circle, HIM 758, Boston, MA 02115, USA.
PMID: 18591254 DOI: 10.1128/MCB.00479-08

Abstract

Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.

References

  1. Cancer Res. 2005 Oct 15;65(20):9398-405 [PMID: 16230403]
  2. Science. 2007 Mar 16;315(5818):1576-9 [PMID: 17322030]
  3. Cell. 2001 Dec 14;107(6):789-800 [PMID: 11747814]
  4. Nucleic Acids Res. 2003 Feb 15;31(4):e15 [PMID: 12582260]
  5. Mol Cell Biol. 2007 Mar;27(5):1859-67 [PMID: 17194750]
  6. Nucleic Acids Res. 2006 May 11;34(8):2294-304 [PMID: 16690972]
  7. J Biol Chem. 2008 Jan 11;283(2):1026-33 [PMID: 17991735]
  8. Cell. 2007 Jun 29;129(7):1401-14 [PMID: 17604727]
  9. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D140-4 [PMID: 16381832]
  10. Oncol Rep. 2007 Jan;17(1):123-8 [PMID: 17143488]
  11. Nat Genet. 2005 May;37(5):495-500 [PMID: 15806104]
  12. Nature. 2007 Oct 11;449(7163):682-8 [PMID: 17898713]
  13. RNA. 2004 Oct;10(10):1507-17 [PMID: 15383676]
  14. Nature. 2005 Feb 17;433(7027):769-73 [PMID: 15685193]
  15. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20820-5 [PMID: 18093951]
  16. Cancer Metastasis Rev. 2007 Dec;26(3-4):675-83 [PMID: 17828469]
  17. Biochem Biophys Res Commun. 2000 May 10;271(2):544-52 [PMID: 10799332]
  18. PLoS Biol. 2004 Nov;2(11):e363 [PMID: 15502875]
  19. Mol Cell. 2007 Jul 6;27(1):91-105 [PMID: 17612493]
  20. Front Biosci. 2003 Jan 01;8:e261-9 [PMID: 12456313]
  21. Mol Cell. 2006 May 19;22(4):553-60 [PMID: 16713585]
  22. Oncogene. 2004 Apr 22;23(19):3308-16 [PMID: 15064729]
  23. Blood. 2007 Aug 15;110(4):1330-3 [PMID: 17496199]
  24. Eur J Cancer. 2004 Jul;40(10):1617-23 [PMID: 15196549]
  25. Mol Cell Biol. 2007 Mar;27(6):2240-52 [PMID: 17242205]
  26. Nat Biotechnol. 2003 Jun;21(6):635-7 [PMID: 12754523]
  27. Apoptosis. 2001 Dec;6(6):479-82 [PMID: 11595838]
  28. Cell Res. 2008 Mar;18(3):350-9 [PMID: 18270520]
  29. Nat Med. 2003 Apr;9(4):407-15 [PMID: 12652295]
  30. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 [PMID: 16461460]
  31. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8904-9 [PMID: 12861074]
  32. Nat Rev Cancer. 2006 Apr;6(4):259-69 [PMID: 16557279]
  33. Oncogene. 2008 Apr 3;27(15):2128-36 [PMID: 17968323]
  34. Oncogene. 2007 Apr 26;26(19):2799-803 [PMID: 17072344]
  35. J Neurosurg. 2001 Jun;94(6):978-84 [PMID: 11409528]
  36. Br J Cancer. 1999 Mar;79(9-10):1347-55 [PMID: 10188875]
  37. Eur J Cancer. 2005 Nov;41(17):2760-8 [PMID: 16256342]
  38. Oncogene. 2006 Oct 9;25(46):6188-96 [PMID: 17028598]
  39. Nat Rev Cancer. 2007 Nov;7(11):819-22 [PMID: 17914404]
  40. Nat Med. 2001 Jun;7(6):743-8 [PMID: 11385514]
  41. Cancer Res. 2007 Oct 1;67(19):8994-9000 [PMID: 17908999]
  42. Nat Protoc. 2007;2(2):329-33 [PMID: 17406593]
  43. Gastroenterology. 2007 Aug;133(2):647-58 [PMID: 17681183]
  44. Clin Sci (Lond). 2006 Mar;110(3):279-91 [PMID: 16464170]
  45. Mol Ther. 2005 Jul;12(1):144-52 [PMID: 15963930]
  46. Cell. 2005 Jan 14;120(1):15-20 [PMID: 15652477]
  47. Brain Pathol. 2003 Oct;13(4):431-9 [PMID: 14655749]
  48. Methods. 2001 Dec;25(4):402-8 [PMID: 11846609]
  49. Genes Dev. 2008 Feb 15;22(4):449-62 [PMID: 18258752]
  50. N Engl J Med. 2008 Jan 31;358(5):502-11 [PMID: 18234754]
  51. EMBO J. 2001 Mar 1;20(5):998-1009 [PMID: 11230124]
  52. J Biol Chem. 2006 Apr 14;281(15):10337-46 [PMID: 16469749]
  53. Cancer Cell. 2006 Mar;9(3):157-73 [PMID: 16530701]
  54. Nature. 2007 Jun 28;447(7148):1130-4 [PMID: 17554337]
  55. Annu Rev Pathol. 2006;1:97-117 [PMID: 18039109]
  56. J Biol Chem. 2007 May 11;282(19):14328-36 [PMID: 17363372]
  57. Cancer Res. 2005 Jul 15;65(14):6029-33 [PMID: 16024602]
  58. J Cell Biochem. 2006 Sep 1;99(1):156-67 [PMID: 16791855]
  59. Brain Pathol. 1999 Jul;9(3):469-79 [PMID: 10416987]
  60. Cancer Cell. 2006 Apr;9(4):287-300 [PMID: 16616334]

Grants

  1. P50 CA086355/NCI NIH HHS
  2. R21 CA116141/NCI NIH HHS
  3. P50 CA86355-04/NCI NIH HHS
  4. R21CA116141/NCI NIH HHS

MeSH Term

Animals
Apoptosis
Base Sequence
Cell Line, Tumor
Cell Movement
Disease Progression
Down-Regulation
Enzyme Inhibitors
Extracellular Matrix
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes, Neoplasm
Glioma
Humans
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Mice
MicroRNAs
Molecular Sequence Data
Neoplasm Invasiveness
Neoplasm Transplantation
Oligonucleotide Array Sequence Analysis
RNA, Messenger

Chemicals

Enzyme Inhibitors
MIRN21 microRNA, human
Matrix Metalloproteinase Inhibitors
MicroRNAs
RNA, Messenger
Matrix Metalloproteinases
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 12

Word Cloud

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