Journal
ONCOTARGET
Volume 6, Issue 13, Pages 11023-11037Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3433
Keywords
microRNA; B-cell; lymphoma; leukemia; c-Myc
Categories
Funding
- National Institutes of Health [R01CA166450-01, K08CA133521, AI-28697, P30CA016042]
- Sidney Kimmel Foundation for Cancer Research [SKF-11-013]
- Eugene V. Cota-Robles Grant
- institutional Tumor Immunology training Grant [NIH T32CA009120]
- National Institute of Health [NIH T32CA009056]
- Eugene V. Cota-Robles Fellowship from UCLA
- National Science Foundation
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
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miR-146a is a NF-kappa B 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-kappa B 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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