| First Author | Jin HY | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 17 | Pages | 2377-91 |
| PubMed ID | 23921550 | Mgi Jnum | J:200069 |
| Mgi Id | MGI:5506955 | Doi | 10.1038/emboj.2013.178 |
| Citation | Jin HY, et al. (2013) MicroRNA-17 approximately 92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. EMBO J 32(17):2377-91 |
| abstractText | MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17 approximately 92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17 approximately 92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17 approximately 92. We experimentally identified miR-17 approximately 92 target genes by PAR-CLIP and validated select target genes in miR-17 approximately 92 transgenic mice. These analyses demonstrate that miR-17 approximately 92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NFkappaB pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17 approximately 92-driven lymphoma cells exhibited constitutive activation of the PI3K and NFkappaB pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17 approximately 92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation. |
