NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6
NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6
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NEAT1 通过调节 microRNA-122 和 Kruppel 样因子 6 加速肝纤维化的进展
DOI：
10.1007/s00109-017-1586-5
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发表时间：
2017-11-01
影响因子：
4.7
通讯作者：
Zheng, Jianjian
中科院分区：
文献类型：
--
作者：
Yu, Fujun;Jiang, Zhe;Zheng, Jianjian
长链非编码RNA（longnon-codingRNA，lncRNA）参与细胞增殖、凋亡、分化和存活等重要的生物学过程。最近，核旁斑装配转录本1（NEAT 1），一种新的lncRNA，在肿瘤中起着重要的调节作用。然而，NEAT 1在肝纤维化中的生物学作用在很大程度上是未知的。在这项研究中，NEAT 1的作用，探讨在原代小鼠肝星状细胞（HSC）和四氯化碳（CCl 4）诱导的小鼠肝纤维化模型。我们发现NEAT 1的表达在CCl 4诱导的小鼠和活化的HSC中显著增加。NEAT 1的缺失抑制了体内和体外的肝纤维化。相反，NEAT 1过表达加速HSC活化，包括增加细胞增殖和胶原蛋白表达。进一步的研究表明microRNA-122（miR-122）-Kruppel样因子6（KLF 6）轴参与了NEAT 1对HSC活化的影响。NEAT 1对HSC活化的作用几乎被miR-122模拟物或KLF 6敲低所阻断。有趣的是，NEAT 1和KLF 6都是miR-122的靶点。此外，miR-122导致NEAT 1水平显著降低，而NEAT 1过表达导致miR-122表达抑制。Pull-down分析证实了miR-122和NEAT 1之间的直接相互作用。NEAT 1通过miR-122-KLF 6轴促进HSC活化。在人类肝纤维化样本中，NEAT 1水平的增加与肝纤维化标志物呈正相关。总之，我们公开了一种新的NEAT 1-miR-122-KLF 6信号级联及其在肝纤维化中的意义。
Long non-coding RNAs (lncRNAs) have been reported to be involved in many important biological processes including proliferation, apoptosis, differentiation, and survival. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1), a novel lncRNA, serves as a crucial regulator in tumors. However, the biological role of NEAT1 in liver fibrosis is largely unknown. In this study, the role of NEAT1 was explored in primary mouse hepatic stellate cells (HSCs) and carbon tetrachloride (CCl4)-induced mouse liver fibrosis models. We found that NEAT1 expression was significantly increased in CCl4-induced mice and activated HSCs. Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro. Conversely, NEAT1 overexpression accelerated HSC activation, including increased cell proliferation and collagen expression. Further studies indicated that the microRNA-122 (miR-122)-Kruppel-like factor 6 (KLF6) axis was involved in the effects of NEAT1 on HSC activation. The effects of NEAT1 on HSC activation were almost blocked down by miR-122 mimics or KLF6 knockdown. Interestingly, both NEAT1 and KLF6 are targets of miR-122. In addition, miR-122 led to a significant reduction in NEAT1 level while NEAT1 overexpression resulted in the suppression of miR-122 expression. Pull-down assay confirmed a direct interaction between miR-122 and NEAT1. NEAT1 contributes to HSC activation via the miR-122-KLF6 axis. In human fibrotic liver samples, increased NEAT1 levels positively correlated with liver fibrosis markers. In conclusion, we disclose a novel NEAT1-miR-122-KLF6 signaling cascade and its implication in liver fibrosis.