The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors.
Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Paul A
PA
Northcott
Africa
A
Fernandez-L
John P
JP
Hagan
David W
DW
Ellison
Wesia
W
Grajkowska
Yancey
Y
Gillespie
Richard
R
Grundy
Timothy
T
Van Meter
James T
JT
Rutka
Carlo M
CM
Croce
Anna Marie
AM
Kenney
Michael D
MD
Taylor
D000328:Adult; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005784:Gene Amplification; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D005810:Multigene Family; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation
D053823:Hedgehog Proteins; C000715470:MAS1 protein, human; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human