The miR-17 similar to 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma

Uziel, T., Karginov, F. V., Xie, S. Q., Parker, J. S., Wang, Y. D., Gajjar, A., He, L., Ellison, D., Gilbertson, R. J., Hannon, G. J., Roussel, M. F. (February 2009) The miR-17 similar to 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proceedings of the National Academy of Sciences of the United States of America, 106 (8). pp. 2812-2817. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/19196975

DOI: 10.1073/pnas.0809579106

Abstract

Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Because microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using 2 spontaneous mouse MB models with specific initiating mutations, Ink4c(-/-); Ptch1(+/-) and Ink4c(-/-); p53(-/-). We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, 9 were encoded by the miR-17 similar to 92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that 3 miR-17 similar to 92 cluster miRNAs (miR-92, miR-19a, and miR-20) were also overexpressed in human MBs with a constitutively activated Sonic Hedgehog (SHH) signaling pathway, but not in other forms of the disease. To test whether the miR-17 similar to 92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c(-/-); Ptch1(+/-) mice. These, but not similarly engineered cells from Ink4c(-/-); p53(-/-) mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17 similar to 92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17 similar to 92 cluster and the SHH signaling pathway in the development of MBs in mouse and man.

Item Type:	Paper
Uncontrolled Keywords:	cerebellum microRNAs oncomiR1 granule neuron progenitors POSTTRANSCRIPTIONAL REGULATION MICRORNA EXPRESSION GENETIC ALTERATIONS CANCER HOMOLOG REVEALS DISEASE GROWTH TUMORS
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics organs, tissues, organelles, cell types and functions > organs types and functions > brain bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
CSHL Authors:	Hannon, Gregory J. Karginov, Fedor V.
Communities:	CSHL labs > Hannon lab CSHL Post Doctoral Fellows
Depositing User:	Matt Covey
Date:	24 February 2009
Date Deposited:	20 Feb 2013 21:15
Last Modified:	05 Jan 2018 20:15
PMCID:	PMC2636735
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/27413

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