Journal of Neuro-Oncology

, Volume 90, Issue 1, pp 1–7 | Cite as

Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma

  • Jessica Pierson
  • Bruce Hostager
  • Rong Fan
  • Rajeev Vibhakar
Lab Investigaton - Human/Animal Tissue

Abstract

Despite recent advances in treatment medulloblastoma continues to remain a vexing problem. Recently increased expression of cyclin dependent kinase 6 (CDK6) was identified as an adverse prognostic marker in medulloblastoma. Genomic amplification accounts for some, but not all of the CDK6 over-expression. We hypothesized that CDK6 expression is also regulated by microRNAs in medulloblastoma. We identified putative miR sites in the CDK6 including microRNA 124a, a brain enriched microRNA. Expression of miR 124a was significantly decreased in medulloblastoma cells compared to normal adult cerebellum. Functional association between miR 124a and CDK6 in medulloblastoma was established using luciferase assays. Additionally, re-expression of miR 124a in medulloblastoma cells decreased expression of CDK6 protein. Transfection of miR 124 significantly decreases medulloblastoma cell growth but does not alter apoptosis. Furthermore, in patient samples expression of miR 124a is significantly decreased. Our data strongly indicate that CDK6 is regulated by microRNA 124 in medulloblastoma and that miR 124 modulates medulloblastoma cell growth.

Keywords

Medulloblastoma Cyclin Dependent Kinase 6 MicroRNA 124 

References

  1. 1.
    Rutka JT et al (2004) Advances in the treatment of pediatric brain tumors. Expert Rev Neurother 4:879–893CrossRefPubMedGoogle Scholar
  2. 2.
    Packer RJ, Cogen P, Vezina G, Rorke LB (1999) Medulloblastoma: clinical and biologic aspects. Neuro-oncology 1:232–250PubMedGoogle Scholar
  3. 3.
    Packer RJ, Rood BR, MacDonald TJ (2003) Medulloblastoma: present concepts of stratification into risk groups. Pediatr Neurosurg 39:60–67CrossRefPubMedGoogle Scholar
  4. 4.
    Larouche V, Huang A, Bartels U, Bouffet E (2007) Tumors of the central nervous system in the first year of life. Pediatr Blood Cancer 49:1074–1082CrossRefPubMedGoogle Scholar
  5. 5.
    Mendrzyk F et al (2005) Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol 23:8853–8862CrossRefPubMedGoogle Scholar
  6. 6.
    Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641CrossRefPubMedGoogle Scholar
  7. 7.
    Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9:13–22CrossRefPubMedGoogle Scholar
  8. 8.
    Lai EC (2005) miRNAs: whys and wherefores of miRNA-mediated regulation. Curr Biol 15:R458–R460CrossRefPubMedGoogle Scholar
  9. 9.
    Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355CrossRefPubMedGoogle Scholar
  10. 10.
    Du T, Zamore PD (2005) microPrimer: the biogenesis and function of microRNA. Development 132:4645–4652CrossRefPubMedGoogle Scholar
  11. 11.
    Giraldez AJ et al (2006) Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312:375–379CrossRefGoogle Scholar
  12. 12.
    He L et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833CrossRefPubMedGoogle Scholar
  13. 13.
    Costinean S et al (2006) Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA 103:7024–7029CrossRefPubMedGoogle Scholar
  14. 14.
    Welch C, Chen Y, Stallings RL (2007) MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 26:5017–5022Google Scholar
  15. 15.
    Vibhakar R et al (2007) Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma. Neuro-oncology 9:135–144CrossRefPubMedGoogle Scholar
  16. 16.
    Borchert GM, Lanier W, Davidson BL (2006) RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13:1097–1101CrossRefPubMedGoogle Scholar
  17. 17.
    Grimson A et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105CrossRefPubMedGoogle Scholar
  18. 18.
    Krek A et al (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500CrossRefPubMedGoogle Scholar
  19. 19.
    Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34:D140–D144CrossRefPubMedGoogle Scholar
  20. 20.
    Lim LP et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773CrossRefPubMedGoogle Scholar
  21. 21.
    Conaco C, Otto S, Han JJ, Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci USA 103:2422–2427CrossRefPubMedGoogle Scholar
  22. 22.
    Peart MJ et al (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 102:3697–3702CrossRefPubMedGoogle Scholar
  23. 23.
    Cheng AM, Byrom MW, Shelton J, Ford LP (2005) Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 33:1290–1297CrossRefPubMedGoogle Scholar
  24. 24.
    Kosik KS, Krichevsky AM (2005) The elegance of the MicroRNAs: a neuronal perspective. Neuron 47:779–782CrossRefPubMedGoogle Scholar
  25. 25.
    Hohjoh H, Fukushima T (2007) Expression profile analysis of microRNA (miRNA) in mouse central nervous system using a new miRNA detection system that examines hybridization signals at every step of washing. Gene 391:39–44CrossRefPubMedGoogle Scholar
  26. 26.
    Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS (2003) A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9:1274–1281CrossRefPubMedGoogle Scholar
  27. 27.
    Deo M, Yu JY, Chung KH, Tippens M, Turner DL (2006) Detection of mammalian microRNA expression by in situ hybridization with RNA oligonucleotides. Dev Dyn 235:2538–2548CrossRefPubMedGoogle Scholar
  28. 28.
    Majumder S (2006) REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle 5:1929–1935Google Scholar
  29. 29.
    Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21:744–749CrossRefPubMedGoogle Scholar
  30. 30.
    Lujambio A et al (2007) Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 67:1424–1429CrossRefPubMedGoogle Scholar
  31. 31.
    Grossel MJ, Hinds PW (2006) Beyond the cell cycle: a new role for Cdk6 in differentiation. J Cell Biochem 97:485–493CrossRefPubMedGoogle Scholar
  32. 32.
    Matushansky I, Radparvar F, Skoultchi AI (2000) Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1. Proc Natl Acad Sci USA 97:14317–14322CrossRefPubMedGoogle Scholar
  33. 33.
    Dews M et al (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38:1060–1065Google Scholar
  34. 34.
    Yu F et al (2007) let-7 Regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Jessica Pierson
    • 1
  • Bruce Hostager
    • 1
  • Rong Fan
    • 1
  • Rajeev Vibhakar
    • 1
  1. 1.Department of PediatricsUniversity of Iowa Children’s Hospital, University of IowaIowa CityUSA

Personalised recommendations