Details

Autor(en) / Beteiligte

• Jin, Hyun Yong
• Oda, Hiroyo
• Lai, Maoyi
• Skalsky, Rebecca L
• Bethel, Kelly
• Shepherd, Jovan
• Kang, Seung Goo
• Liu, Wen-Hsien
• Sabouri-Ghomi, Mohsen
• Cullen, Bryan R
• Rajewsky, Klaus
• Xiao, Changchun

Titel

MicroRNA-1792 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways

Ist Teil von

• The EMBO journal, 2013-08, Vol.32 (17), p.2377-2391

Erscheinungsjahr

2013

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-1792 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-1792 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-1792. We experimentally identified miR-1792 target genes by PAR-CLIP and validated select target genes in miR-1792 transgenic mice. These analyses demonstrate that miR-1792 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NF Kappa B pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-1792-driven lymphoma cells exhibited constitutive activation of the PI3K and NF Kappa B pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-1792 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.