MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20)

Proc Natl Acad Sci U S A. 2012 May 15;109(20):7865-70. doi: 10.1073/pnas.1200081109. Epub 2012 May 1.

Abstract

Constitutive activation of the NF-κB pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether microRNA dysfunction can contribute to these events remains unclear. Starting from an integrative screening strategy, we uncovered that the negative NF-κB regulator TNFAIP3 is a direct target of miR-125a and miR-125b, which are commonly gained and/or overexpressed in DLBCL. Ectopic expression of these microRNAs in multiple cell models enhanced K63-linked ubiquitination of proximal signaling complexes and elevated NF-κB activity, leading to aberrant expression of its transcriptional targets and the development of a proproliferative and antiapoptotic phenotype in malignant B cells. Concordantly, genetic inhibition of miR-125a/miR-125b blunted NF-κB signals, whereas rescue assays and genetic modulation of a TNFAIP3-null model defined the essential role of the TNFAIP3 targeting on miR-125a/miR-125b-mediated lymphomagenesis. Importantly, miR-125a/mir-125b effects on TNFAIP3 expression and NF-κB activity were confirmed in a well-characterized cohort of primary DLBCLs. Our data delineate a unique epigenetic model for aberrant activation of the NF-κB pathway in cancer and provide a coherent mechanism for the role of these miRNAs in immune cell activation and hematopoiesis. Further, as miR-125b is a direct NF-κB transcriptional target, our results suggest the presence of a positive self-regulatory loop whereby termination of TNFAIP3 function by miR-125 could strengthen and prolong NF-κB activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Profiling
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MicroRNAs / metabolism*
  • NF-kappa B / metabolism*
  • Nuclear Proteins / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Statistics, Nonparametric
  • Subcellular Fractions
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MIRN125 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Nuclear Proteins
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3