miR-17∼92 cooperates with RB pathway mutations to promote retinoblastoma
- Karina Conkrite1,
- Maggie Sundby1,
- Shizuo Mukai2,
- J. Michael Thomson3,
- David Mu4,5,
- Scott M. Hammond3 and
- David MacPherson1,6
- 1Department of Embryology, Carnegie Institution, Baltimore, Maryland 21218, USA;
- 2Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA;
- 3Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina School at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- 4Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA;
- 5Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
Abstract
The miR-17∼92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17∼92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17∼92 genomic amplifications in murine retinoblastoma and high expression of miR-17∼92 in human retinoblastoma. While miR-17∼92 was dispensable for mouse retinal development, miR-17∼92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17∼92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17∼92 increased the proliferative capacity of Rb/p107-deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR-17∼92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17∼92 are context-specific and provide new insights into miR-17∼92 function as an RB-collaborating gene in cancer.
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Footnotes
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↵6 Corresponding author.
E-mail macpherson{at}ciwemb.edu.
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.17027411.
- Received May 16, 2011.
- Accepted July 8, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press