Pleiotropic effects of miR-183̃96̃182 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

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Medulloblastomas are the most common malignant brain tumors in children. Several large-scale genomic studies have detailed their heterogeneity, defining multiple subtypes with uniquemolecular profiles and clinical behavior. Increased expression of the miR-183̃96̃182 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-183̃96̃182 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 fullmiR- 183̃96̃182 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 tomesenchymal 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 phenocopiesmiR-183 cluster knockdown. Thus, the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma.

Original languageEnglish (US)
Pages (from-to)539-552
Number of pages14
JournalActa Neuropathologica
Issue number4
Publication statusPublished - Apr 1 2012
Externally publishedYes

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