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

被引:233
作者
Northcott, Paul A. [3 ]
Fernandez-L, Africa [1 ]
Hagan, John P. [2 ]
Ellison, David W. [4 ]
Grajkowska, Wesia [5 ]
Gillespie, Yancey [7 ]
Grundy, Richard [6 ]
Van Meter, Timothy [8 ]
Rutka, James T. [3 ]
Croce, Carlo M. [2 ]
Kenney, Anna Marie [1 ]
Taylor, Michael D. [3 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA
[2] Ohio State Univ, Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[3] Univ Toronto, Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Div Neurosurg,Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada
[4] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA
[5] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland
[6] Univ Nottingham, Nottingham NG7 2RD, England
[7] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA
[8] Virginia Commonwealth Univ, Med Coll Virginia, Dept Neurosurg, Richmond, VA 23298 USA
关键词
NEURONAL PRECURSORS; EXPRESSION; MICRORNAS; PROLIFERATION; SIGNATURES; DISEASE;
D O I
10.1158/0008-5472.CAN-08-4710
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 tip-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 Glil, 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]
引用
收藏
页码:3249 / 3255
页数:7
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