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

Abstract

Constitutive activation of the NF-κB pathway is associated with diffuse large B-cell lymphoma (DLBCL) pathogenesis, but whether micro-RNA 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/mir125b 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.

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…[95][96][97][98][99][100][101] Other oncomiRs include miR-125a and miR-125b, which aberrantly target TNFAIP3, leading to constitutive NF-kB activation. 102 On the contrary, several key miRNAs that target antiapoptotic genes are downregulated or deleted in lymphoid tumors. For example, miR-15a/16-1 acts as a tumor suppressor in CLL by targeting BCL2.…”

Assessment of microRNA profile of kidney biopsies of patients with lupus nephritis

“…Within the recent two decades, more than 140 conserved miRNAs were discovered that have specific target site on 72 candidate genes for lupus and LN (18). The investigations could show that some miRNAs play a central role in the pathogenesis of LN by reducing production of pro-inflammatory mediators as well as with inhibiting lymphocyte function (19)(20)(21)(22)(23). In the present study, we assessed the expression of three introduced genes including miR638, miR-146a, miR-198 and miR-371 in LN patients.…”

MicroRNAs and lymphomagenesis: a functional review

“…MIR125B down-regulates the expression of IRF4 and PRDM1 (Malumbres et al, 2009), and recently MIR125A/B were shown to directly target TNFAIP3, a negative regulator of the NF-jB pathway. Overexpression of either of these miRNAs were found to increase the aggressiveness of DLBCL cell lines (Kim et al, 2012). Furthermore, a strong correlation between NF-jB activity and expression levels of MIR125A/B in primary DLBCL cases was reported.…”