MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1.
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.
['Contreras|Jorge R|JR|', 'Palanichamy|Jayanth Kumar|JK|', 'Tran|Tiffany M|TM|', 'Fernando|Thilini R|TR|', 'Rodriguez-Malave|Norma I|NI|', 'Goswami|Neha|N|', 'Arboleda|Valerie A|VA|', 'Casero|David|D|', 'Rao|Dinesh S|DS|']
D000818:Animals D017209:Apoptosis D001402:B-Lymphocytes D014408:Biomarkers, Tumor D015153:Blotting, Western D049109:Cell Proliferation D002471:Cell Transformation, Neoplastic D002478:Cells, Cultured D051766:Early Growth Response Protein 1 D005434:Flow Cytometry D015972:Gene Expression Regulation, Neoplastic D059014:High-Throughput Nucleotide Sequencing D006801:Humans D016393:Lymphoma, B-Cell D051379:Mice D018345:Mice, Knockout D008822:Mice, Transgenic D035683:MicroRNAs D016328:NF-kappa B D016271:Proto-Oncogene Proteins c-myc D012333:RNA, Messenger D060888:Real-Time Polymerase Chain Reaction D020133:Reverse Transcriptase Polymerase Chain Reaction
B-cell microRNA c-Myc leukemia lymphoma