Author:
Conkrite Karina,Sundby Maggie,Mukai Shizuo,Thomson J. Michael,Mu David,Hammond Scott M.,MacPherson David
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.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
160 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献