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

• Verfasst von: Weeraratne, Shyamal Dilhan [VerfasserIn]
• Verfasst von: Remke, Marc [VerfasserIn]
• Verfasst von: Pfister, Stefan [VerfasserIn]
• Titel: Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma
• Verf.angabe: 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
• E-Jahr: 2012
• Jahr: 10 March 2012
• Umfang: 14 S.
• Fussnoten: Gesehen am 04.04.2019
• Titel Quelle: Enthalten in: Acta neuropathologica
• Ort Quelle: Berlin : Springer, 1961
• Jahr Quelle: 2012
• Band/Heft Quelle: 123(2012), 4, Seite 539-552
• ISSN Quelle: 1432-0533
• DOI: doi:10.1007/s00401-012-0969-5
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: AKT
• Sach-SW: Apoptosis
• Sach-SW: DNA repair
• Sach-SW: EMT
• Sach-SW: Medulloblastoma
• Sach-SW: Microrna
• Sach-SW: Migration
• Sach-SW: miR182
• Sach-SW: miR183
• Sach-SW: miR96
• Sach-SW: mTOR
• K10plus-PPN: 1662806620

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.