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Acta Neuropathologica

, Volume 123, Issue 4, pp 539–552 | Cite as

Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

  • Shyamal Dilhan Weeraratne
  • Vladimir Amani
  • Natalia Teider
  • Jessica Pierre-Francois
  • Dominic Winter
  • Min Jeong Kye
  • Soma Sengupta
  • Tenley Archer
  • Marc Remke
  • Alfa H. C. Bai
  • Peter Warren
  • Stefan M. Pfister
  • Judith A. J. Steen
  • Scott L. Pomeroy
  • Yoon-Jae Cho
Original Paper

Abstract

Medulloblastomas are the most common malignant brain tumors in children. Several large-scale genomic studies have detailed their heterogeneity, defining multiple subtypes with unique molecular profiles and clinical behavior. Increased expression of the miR-183~96~182 cluster of microRNAs has been noted in several subgroups, including the most clinically aggressive subgroup associated with genetic amplification of MYC. To understand the contribution of miR-183~96~182 to the pathogenesis of this aggressive subtype of medulloblastoma, we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells. Knockdown of the full miR-183~96~182 cluster results in enrichment of genes associated with apoptosis and dysregulation of the PI3K/AKT/mTOR signaling axis. Conversely, there is a relative enrichment of pathways associated with migration, metastasis and epithelial to mesenchymal transition, as well as pathways associated with dysfunction of DNA repair in cells with preserved miR-183 cluster expression. Immunocytochemistry and FACS analysis confirm induction of apoptosis upon knockdown of the miR-183 cluster. Importantly, cell-based migration and invasion assays verify the positive regulation of cell motility/migration by the miR-183 cluster, which is largely mediated by miR-182. We show that the effects on cell migration induced by the miR-183 cluster are coupled to the PI3K/AKT/mTOR pathway through differential regulation of AKT1 and AKT2 isoforms. Furthermore, we show that rapamycin inhibits cell motility/migration in medulloblastoma cells and phenocopies miR-183 cluster knockdown. Thus, the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma.

Keywords

Medulloblastoma Microrna miR183 miR182 miR96 EMT AKT mTOR Migration Apoptosis DNA repair 

Notes

Acknowledgments

Y.J.C. is funded in part by the St. Baldrick’s Foundation Scholar Award and the Bear Necessities Pediatric Cancer Research Foundation. A.H.B. was funded in part by the German Academic Exchange. This project received support from Grant NIH-R01-CA109467.

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

401_2012_969_MOESM1_ESM.pdf (105 kb)
Supplementary material 1 (PDF 104 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Shyamal Dilhan Weeraratne
    • 1
  • Vladimir Amani
    • 1
  • Natalia Teider
    • 1
  • Jessica Pierre-Francois
    • 1
  • Dominic Winter
    • 2
  • Min Jeong Kye
    • 1
    • 2
  • Soma Sengupta
    • 1
  • Tenley Archer
    • 1
  • Marc Remke
    • 3
    • 4
  • Alfa H. C. Bai
    • 3
  • Peter Warren
    • 2
  • Stefan M. Pfister
    • 3
    • 4
  • Judith A. J. Steen
    • 1
    • 2
  • Scott L. Pomeroy
    • 1
  • Yoon-Jae Cho
    • 1
    • 5
    • 6
  1. 1.Department of NeurologyChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  2. 2.Department of PathologyChildren’s Hospital BostonBostonUSA
  3. 3.German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of Pediatric Hematology and OncologyHeidelberg University HospitalHeidelbergGermany
  5. 5.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  6. 6.Department of NeurosurgeryStanford University School of MedicineStanfordUSA

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