MicroRNAs miR-125a and miR-125b constitutively activate the NF-?B pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20).
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ABSTRACT: Constitutive activation of the NF-?B 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-?B 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-?B 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-?B 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-?B activity were confirmed in a well-characterized cohort of primary DLBCLs. Our data delineate a unique epigenetic model for aberrant activation of the NF-?B 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-?B 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-?B activity.
SUBMITTER: Kim SW
PROVIDER: S-EPMC3356650 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
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