Journal
EMBO JOURNAL
Volume 27, Issue 19, Pages 2616-2627Publisher
WILEY
DOI: 10.1038/emboj.2008.172
Keywords
cancer; expression profiling; Hedgehog; microRNA; post-transcriptional control
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro [GGP07118]
- Ministry of University and Research (PRIN)
- Ministry of Health
- Cenci-Bolognetti Foundation
- Rome Oncogenomic Center
- Center of Excellence BEMM
- 6th Framework Programme of the European Commission
- SIROCCO and RIGHT Integrated Projects [LSHG-CT-2006-037900, LSHB-CT-2004005276]
- ESF project 'NuRNASu'
- Fondazione Telethon Funding Source: Custom
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MicroRNAs (miRNA) are crucial post-transcriptional regulators of gene expression and control cell differentiation and proliferation. However, little is known about their targeting of specific developmental pathways. Hedgehog (Hh) signalling controls cerebellar granule cell progenitor development and a subversion of this pathway leads to neoplastic transformation into medulloblastoma (MB). Using a miRNA high-throughput profile screening, we identify here a downregulated miRNA signature in human MBs with high Hh signalling. Specifically, we identify miR-125b and miR-326 as suppressors of the pathway activator Smoothened together with miR-324-5p, which also targets the downstream transcription factor Gli1. Downregulation of these miRNAs allows high levels of Hh-dependent gene expression leading to tumour cell proliferation. Interestingly, the downregulation of miR-324-5p is genetically determined by MB-associated deletion of chromosome 17p. We also report that whereas miRNA expression is downregulated in cerebellar neuronal progenitors, it increases alongside differentiation, thereby allowing cell maturation and growth inhibition. These findings identify a novel regulatory circuitry of the Hh signalling and suggest that misregulation of specific miRNAs, leading to its aberrant activation, sustain cancer development.
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