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 Journal Article


Authors: Northcott, P. A.; Fernandez-L, A.; Hagan, J. P.; Ellison, D. W.; Grajkowska, W.; Gillespie, Y.; Grundy, R.; Meter, T. V.; Rutka, J. T.; Croce, C. M.; Kenney, A. M.; Taylor, M. D.
Article Title: 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
Abstract: 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 GUI, 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. © 2009 American Association for Cancer Research.
Keywords: signal transduction; adult; child; human cell; single nucleotide polymorphism; cell proliferation; animals; mice; cerebellum; proto oncogene; microrna; gene amplification; gene expression; gene expression profiling; sonic hedgehog protein; hedgehog proteins; genotype; neurons; fluorescence in situ hybridization; medulloblastoma; cell growth processes; stem cells; upregulation; tissue microarray; up-regulation; micrornas; proto-oncogene proteins c-myc; cerebellar neoplasms; oncogene c myb; oncogene myc; pediatrics; multigene family
Journal Title: Cancer Research
Volume: 69
Issue: 8
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2009-04-15
Start Page: 3249
End Page: 3255
Language: English
DOI: 10.1158/0008-5472.can-08-4710
PUBMED: 19351822
PROVIDER: scopus
PMCID: PMC2836891
DOI/URL:
Notes: --- - "Cited By (since 1996): 45" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"
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  1. Anna Marie Kenney
    34 Kenney