Abstract
Hyper activity of protooncogene c-Myc is one of the hallmarks of highly aggressive lymphomas. However, the mechanism of how c-Myc is subjected to activation and amplification is still not well defined. In this study, we use gene knockout strategy to show that targeted depletion of a well-conserved microRNA gene locus miR-144/451 initiates tumorigenesis including B-lymphoma development in aged mice. This is due, at least in part, to the direct activation of the c-Myc gene by loss of miR-144/451 expression in hematopoietic cells. Moreover, oncoprotein c-Myc inversely regulates miR-144/451 expression by directly binding to the miR-144/451 promoter region, forming a miRNA-Myc positive feedback loop to safeguard the high level of c-Myc in B-lymphocytes. We also demonstrate that this miRNA-Myc crosstalk is disrupted in human diffuse large B-cell lymphomas with aberrant c-Myc expression. Therefore, our findings provide strong evidence, for the first time, that deficiency of miR-144/451 expression may play a bona fide role in derepression of silenced c-Myc, which contributes to tumor development including B-lymphomagenesis.
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1 Department of Pathology, Jiangdu People’s Hospital, Yangzhou University, Yangzhou, China
2 Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of Medicine, Yangzhou, Jiangsu Province, China
3 Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of Medicine, Yangzhou, Jiangsu Province, China; Institute of Translational Medicine, Yangzhou University School of Medicine, Yangzhou, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China