title: MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1.
abstract: miR-146a is a NF-κB induced microRNA that serves as a feedback regulator of this critical pathway. In mice, deficiency of miR-146a results in hematolymphoid cancer at advanced ages as a consequence of constitutive NF-κB activity. In this study, we queried whether the deficiency of miR-146a contributes to B-cell oncogenesis. Combining miR-146a deficiency with transgenic expression of c-Myc led to the development of highly aggressive B-cell malignancies. Mice transgenic for c-Myc and deficient for miR-146a were characterized by significantly shortened survival, increased lymph node involvement, differential involvement of the spleen and a mature B-cell phenotype. High-throughput sequencing of the tumors revealed significant dysregulation of approximately 250 genes. Amongst these, the transcription factor Egr1 was consistently upregulated in mice deficient for miR-146a. Interestingly, transcriptional targets of Egr1 were enriched in both the high-throughput dataset and in a larger set of miR-146a-deficient tumors. miR-146a overexpression led to downregulation of Egr1 and downstream targets with concomitant decrease in cell growth. Direct targeting of the human EGR1 by miR-146a was seen by luciferase assay. Together our findings illuminate a bona fide role for miR-146a in the modulation of B-cell oncogenesis and reveal the importance of understanding microRNA function in a cell- and disease-specific context.
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, CA, USA.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Contreras
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Jayanth Kumar
authors.initials: JK
authors.lastname: Palanichamy
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Tran
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Thilini R
authors.initials: TR
authors.lastname: Fernando
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, CA, USA.
authors.forename: Norma I
authors.initials: NI
authors.lastname: Rodriguez-Malave
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Goswami
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Arboleda
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Casero
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.|Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D051766:Early Growth Response Protein 1; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C489428:Myc protein, mouse; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger
keywords: B-cell; c-Myc; leukemia; lymphoma; microRNA