MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1

• Published in: Oncotarget 2015-05, Vol.6 (13), p.11023-11037
• Main Authors: Contreras, Jorge R, Palanichamy, Jayanth Kumar, Tran, Tiffany M, Fernando, Thilini R, Rodriguez-Malave, Norma I, Goswami, Neha, Arboleda, Valerie A, Casero, David, Rao, Dinesh S
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Cells, Cultured; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Flow Cytometry; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Lymphoma, B-Cell - etiology; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Mice; Mice, Knockout; Mice, Transgenic; MicroRNAs - physiology; NF-kappa B - genetics; NF-kappa B - metabolism; Proto-Oncogene Proteins c-myc - physiology; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3433

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.