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

¹Division 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; ²Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, Ohio; ⁴Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee; ⁵Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland; ⁶Department of Surgery, University of Alabama, Birmingham, Alabama; ⁷University of Nottingham, Nottingham, United Kingdom; and ⁸Department of Neurosurgery, Medical College of Virginia, Richmond, Virginia

^* To whom correspondence should be addressed. E-mail: kenneya{at}mskcc.org.

	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 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. [Cancer Res 2009;69(8):3249–55]

Key Words: medulloblastoma, miR-17/92, microRNA, sonic hedgehog, cerebellar neural precursor, N-myc

This article has been cited by other articles:

				A. Fernandez-L, P. A. Northcott, J. Dalton, C. Fraga, D. Ellison, S. Angers, M. D. Taylor, and A. M. Kenney YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation Genes & Dev., December 1, 2009; 23(23): 2729 - 2741. [Abstract] [Full Text] [PDF]

				N. V. Varlakhanova and P. S. Knoepfler Acting Locally and Globally: Myc's Ever-Expanding Roles on Chromatin Cancer Res., October 1, 2009; 69(19): 7487 - 7490. [Abstract] [Full Text] [PDF]