A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis
A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis
复制标题
c-Myc-MicroRNA 功能反馈环影响肝癌发生
DOI：
10.1002/hep.26302
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Li, Youjun
中科院分区：
文献类型：
--
作者：
Han, Han;Sun, Dan;Li, Youjun
c-Myc（Myc）在正常肝脏发育和肿瘤发生中起重要作用。我们在这里表明，Myc是病理激活的，并为促进人类肝细胞癌（HCC）所必需的。Myc通过一种新的microRNA（miRNA）介导的反馈环诱导HCC，该反馈环由miR-148 a-5 p、miR-363- 3 p和泛素特异性蛋白酶28（USP 28）组成。Myc直接与两种miRNA启动子中的保守区域结合并抑制其表达。miR-148 a-5 p直接靶向并抑制Myc，而miR-363- 3 p通过直接靶向并抑制USP 28使Myc不稳定。抑制miR-148 a-5 p或miR-363- 3 p通过促进G1期至S期进展诱导肝细胞肿瘤发生，而激活它们则具有相反的作用。Myc-miRNA反馈环在人HCC中失调结论：这些结果将miR-148 a-5 p和miR-363- 3 p定义为Myc的负调节因子，从而揭示了它们在肝癌发生中迄今未被认识的作用。（肝脏学2013;57：2378-2389）
c-Myc (Myc) plays an important role in normal liver development and tumorigenesis. We show here that Myc is pathologically activated in and essential for promoting human hepatocellular carcinoma (HCC). Myc induces HCC through a novel, microRNA (miRNA)-mediated feedback loop comprised of miR-148a-5p, miR-363-3p, and ubiquitin-specific protease 28 (USP28). Myc directly binds to conserved regions in the promoters of the two miRNAs and represses their expression. miR-148a-5p directly targets and inhibits Myc, whereas miR-363-3p destabilizes Myc by directly targeting and inhibiting USP28. Inhibition of miR-148a-5p or miR-363-3p induces hepatocellular tumorigenesis by promoting G1 to S phase progression, whereas activation of them has the opposite effects. The Myc-miRNA feedback loop is dysregulated in human HCC. Conclusion: These results define miR-148a-5p and miR-363-3p as negative regulators of Myc, thus revealing their heretofore unappreciated roles in hepatocarcinogenesis. (HEPATOLOGY 2013;57:2378-2389)