Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation
Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation
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Lnc-UCID 通过阻止 DHX9 介导的 CDK6 下调促进 G1/S 转变和肝癌生长
DOI：
10.1002/hep.30613
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发表时间：
2019-07-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
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作者：
Wang, Yun-Long;Liu, Jin-Yu;Zhuang, Shi-Mei
尽管已经注释了数千种长非编码RNA（lncRNA），但是只有有限数量的lncRNA被功能性地表征。在这里，我们鉴定了一种致癌lncRNA，命名为lnc-UCID（lncRNA通过与DHX 9相互作用上调CDK 6）。Lnc-UCID在肝细胞癌（HCC）中表达上调，且较高的Lnc-UCID水平与HCC患者较短的无复发生存期相关。功能获得和功能丧失研究均显示，lnc-UCID增强细胞周期蛋白依赖性激酶6（CDK 6）的表达，从而促进G1/S转换和细胞增殖。来自小鼠异种移植物模型的研究显示，来自lnc-UCID沉默的HCC细胞的肿瘤比来自对照细胞的肿瘤具有小得多的尺寸，并且瘤内注射lnc-UCID小干扰RNA抑制异种移植物生长。在机制上，lnc-UCID的850-1030-nt结构域与RNA解旋酶DEAH（Asp-Glu-Ala-His）盒解旋酶9（DHX 9）物理相互作用。另一方面，DHX 9通过与CDK 6 mRNA的3 '非翻译区（3 ' UTR）结合而转录后抑制CDK 6表达。进一步的研究揭示了lnc-UCID通过竞争性结合DHX 9并从CDK 6 -3 ' UTR隔离DHX 9来增强CDK 6表达。在试图探索肝癌中lnc-UCID上调的机制时，我们发现lnc-UCID基因在肝癌中频繁扩增。miR-148 a可与lnc-UCID结合，抑制lnc-UCID的表达。结论：lnc-UCID的上调可能是由于其基因座的扩增和miR-148 a的下调，可以通过阻止DHX 9与CDK 6的相互作用并随后增强CDK 6表达来促进HCC生长。这些发现为lncRNA的生物学功能、细胞周期控制的调控网络以及HCC发展的机制提供了见解，这可能用于抗癌治疗。
Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3 '-untranslated region (3 ' UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3 ' UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.