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MicroRNA-17 similar to 92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways

Academic Article
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Overview

related to degree

  • Jin, Hyun-Yong, Ph.D. in Biology, Scripps Research 2010 - 2016

authors

  • Jin, Hyun-Yong
  • Oda, H.
  • Lai, M.
  • Skalsky, R. L.
  • Bethel, Kelly
  • Shepherd, J.
  • Kang, S. G.
  • Liu, W. H.
  • Sabouri-Ghomi, M.
  • Cullen, B. R.
  • Rajewsky, K.
  • Xiao, Changchun

publication date

  • August 2013

journal

  • EMBO Journal  Journal

abstract

  • MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17~92 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-17~92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17~92. We experimentally identified miR-17~92 target genes by PAR-CLIP and validated select target genes in miR-17~92 transgenic mice. These analyses demonstrate that miR-17~92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NF?B pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17~92-driven lymphoma cells exhibited constitutive activation of the PI3K and NF?B pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17~92 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.
  • MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17~92 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-17~92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17~92. We experimentally identified miR-17~92 target genes by PAR-CLIP and validated select target genes in miR-17~92 transgenic mice. These analyses demonstrate that miR-17~92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NFκB pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17~92-driven lymphoma cells exhibited constitutive activation of the PI3K and NFκB pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17~92 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.

subject areas

  • Animals
  • B-Lymphocytes
  • Burkitt Lymphoma
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Humans
  • Imidazoles
  • Lymphoma
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs
  • Morpholines
  • NF-kappa B
  • Phosphatidylinositol 3-Kinases
  • Quinoxalines
  • Reproducibility of Results
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Identity

PubMed Central ID

  • PMC3771343

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/emboj.2013.178

PubMed ID

  • 23921550
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Additional Document Info

start page

  • 2377

end page

  • 2391

volume

  • 32

issue

  • 17

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