TitlemiR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsKozloski, Goldi A., Jiang Xiaoyu, Bhatt Shruti, Ruiz Jose, Vega Francisco, Shaknovich Rita, Melnick Ari, and Lossos Izidore S.
JournalBlood
Volume127
Issue23
Pagination2856-66
Date Published2016 06 09
ISSN1528-0020
KeywordsAnimals, B-Lymphocytes, Cell Line, Tumor, Cell Transformation, Neoplastic, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs, NF-kappa B, Signal Transduction, Xenograft Model Antitumor Assays
Abstract

<p>Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor κ-light-chain enhancer of activated B-cells (NF-κB) signaling. miR-181a overexpression significantly decreases the expression and activity of key NF-κB signaling components. Moreover, miR-181a decreases DLBCL tumor cell proliferation and survival, and anti-miR-181a abrogates these effects. Remarkably, these effects are augmented in the NF-κB dependent ABC-like subgroup compared with the GC B-cell (GCB)-like DLBCL subgroup. Concordantly, in vivo analyses of miR-181a induction in xenografts results in slower tumor growth rate and prolonged survival in the ABC-like DLBCL xenografts compared with the GCB-like DLBCL. We link these outcomes to relatively lower endogenous miR-181a expression and to NF-κB signaling dependency in the ABC-like DLBCL subgroup. Our findings indicate that miR-181a inhibits NF-κB activity, and that manipulation of miR-181a expression in the ABC-like DLBCL genetic background may result in a significant change in the proliferation and survival phenotype of this malignancy.</p>

DOI10.1182/blood-2015-11-680462
Alternate JournalBlood
PubMed ID26941399