title: miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma.
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.
authors.affiliation: Department of Embryology, Carnegie Institution, Baltimore, Maryland 21218, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Conkrite
authors.forename: Maggie
authors.initials: M
authors.lastname: Sundby
authors.forename: Shizuo
authors.initials: S
authors.lastname: Mukai
authors.forename: J Michael
authors.initials: JM
authors.lastname: Thomson
authors.forename: David
authors.initials: D
authors.lastname: Mu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hammond
authors.forename: David
authors.initials: D
authors.lastname: MacPherson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011247:Pregnancy; D012160:Retina / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D012175:Retinoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107