Department of Pathology, Jiangdu People's Hospital, Yangzhou University, Yangzhou, China.
Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of Medicine, Yangzhou, Jiangsu Province, China.
Oncogene. 2018 Mar;37(10):1293-1307. doi: 10.1038/s41388-017-0055-5. Epub 2017 Dec 29.
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.
原癌基因 c-Myc 的过度激活是高度侵袭性淋巴瘤的特征之一。然而，c-Myc 被激活和扩增的机制仍未得到很好的定义。在这项研究中，我们使用基因敲除策略表明，靶向耗尽 miR-144/451 这一高度保守的 microRNA 基因座，会导致包括老年小鼠 B 细胞淋巴瘤在内的肿瘤发生。这至少部分是由于造血细胞中 miR-144/451 表达的缺失直接激活了 c-Myc 基因。此外，癌蛋白 c-Myc 通过直接结合 miR-144/451 启动子区域，反过来调节 miR-144/451 的表达，形成 miRNA-Myc 正反馈回路，以确保 B 淋巴细胞中 c-Myc 的高水平。我们还证明，这种 miRNA-Myc 串扰在具有异常 c-Myc 表达的人类弥漫性大 B 细胞淋巴瘤中被破坏。因此，我们的研究结果首次提供了强有力的证据，表明 miR-144/451 表达的缺失可能在沉默的 c-Myc 的去抑制中发挥真正的作用，这有助于包括 B 细胞淋巴瘤在内的肿瘤的发生。
