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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-04, Vol.69 (8), p.3249-3255
• Main Authors: NORTHCOTT, Paul A, FERNANDEZ-L, Africa, KENNEY, Anna Marie, TAYLOR, Michael D, HAGAN, John P, ELLISON, David W, GRAJKOWSKA, Wesia, GILLESPIE, Yancey, GRUNDY, Richard, VAN METER, Timothy, RUTKA, James T, CROCE, Carlo M
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antineoplastic agents; Biological and medical sciences; Cell Growth Processes - genetics; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Gene Amplification; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hedgehog Proteins - pharmacology; Humans; Medical sciences; Medulloblastoma - genetics; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; MicroRNAs - biosynthesis; MicroRNAs - genetics; Multigene Family; Neurology; Neurons - drug effects; Neurons - pathology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Signal Transduction; Stem Cells - drug effects; Stem Cells - pathology; Tumors; Tumors of the nervous system. Phacomatoses; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-08-4710

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.