miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma.

Publication Type:

Journal Article

Source:

Genes & development, Volume 25, Issue 16, p.1734-45 (2011)

Keywords:

Animals, Animals, Newborn, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Female, Gene Expression Profiling, Humans, Male, MICE, Mice, Knockout, Mice, Transgenic, MICRORNAS, Multigene Family, Mutation, Oligonucleotide Array Sequence Analysis, Oligonucleotides, Antisense, PREGNANCY, Retina, Retinoblastoma, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Signal Transduction

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.