State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Nucleic Acids Res. 2018 Feb 28;46(4):2012-2029. doi: 10.1093/nar/gkx1254.
Hepatic miR-122 can serve as a pro-apoptotic factor to suppress tumorigenesis. The underlying mechanism, however, remains incompletely understood. Here we present the first evidence that miR-122 promotes hepatocellular carcinoma cell apoptosis through directly silencing the biogenesis of cell survival oncomiR miR-21 at posttranscriptional level. We find that miR-122 is strongly expressed in primary liver cell nucleus but its nuclear localization is markedly decreased in transformed cells particularly in chemoresistant tumor cells. MiRNA profiling and RT-qPCR confirm an inverse correlation between miR-122 and miR-21 in hepatocellular carcinoma tissues/cells, and increasing or decreasing nuclear level of miR-122 respectively reduces or increases miR-21 expression. Mechanistically, nuclear miR-122 suppresses miR-21 maturation via binding to a 19-nt UG-containing recognition element in the basal region of pri-miR-21 and preventing the Drosha-DGCR8 microprocessor's conversion of pri-miR-21 into pre-miR-21. Furthermore, both in vitro and in vivo studies demonstrate that nuclear miR-122 participates in the regulation of HCC cell apoptosis through modulating the miR-21-targeted programmed cell death 4 (PDCD4) signal pathway.
肝 miR-122 可作为促凋亡因子抑制肿瘤发生。然而，其潜在机制尚不完全清楚。本文首次证明，miR-122 通过直接抑制细胞存活致癌 miRNA miR-21 的生物发生，在转录后水平促进肝细胞癌细胞凋亡。我们发现 miR-122 在原代肝细胞核中强烈表达，但在转化细胞，特别是在耐药肿瘤细胞中，其核定位明显减少。miRNA 谱分析和 RT-qPCR 证实了肝癌组织/细胞中 miR-122 和 miR-21 之间的负相关，并且分别增加或减少核 miR-122 的水平会降低或增加 miR-21 的表达。从机制上讲，核 miR-122 通过与 pri-miR-21 基本区域的 19nt UG 富含识别元件结合，阻止 Drosha-DGCR8 微处理器将 pri-miR-21 转化为 pre-miR-21，从而抑制 miR-21 的成熟。此外，体内外研究均表明，核 miR-122 通过调节 miR-21 靶向的程序性细胞死亡 4（PDCD4）信号通路参与 HCC 细胞凋亡的调节。
