title: miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Goldi A
authors.identifier: 0000-0003-4918-1132
authors.initials: GA
authors.lastname: Kozloski
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Molecular and Cellular Pharmacology.
authors.forename: Shruti
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Department of Otolaryngology, and.
authors.forename: Jose
authors.initials: J
authors.lastname: Ruiz
authors.affiliation: Department of Pathology, University of Miami, Miami, FL; and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.affiliation: Department of Pathology and Laboratory Medicine, and.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Molecular and Cellular Pharmacology.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B