MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1
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Jorge R. Contreras1,2, Jayanth Kumar Palanichamy1, Tiffany M. Tran1, Thilini R. Fernando1, Norma I. Rodriguez-Malave1,2, Neha Goswami1, Valerie A. Arboleda1, David Casero1, Dinesh S. Rao1,3,4
1Department of Pathology and Laboratory Medicine, UCLA
2Cellular and Molecular Pathology Ph.D. Program, UCLA
3Jonsson Comprehensive Cancer Center, UCLA
4Broad Stem Cell Research Center, UCLA
Dinesh S. Rao, e-mail: [email protected]
Keywords: microRNA, B-cell, lymphoma, leukemia, c-Myc
Received: January 26, 2015 Accepted: February 24, 2015 Published: April 13, 2015
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.
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