LncRNA-MEG3 inhibits activation of hepatic stellate cells through SMO protein and miR-212.
LncRNA-MEG3 inhibits activation of hepatic stellate cells through SMO protein and miR-212.
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LncRNA-MEG3 通过 SMO 蛋白和 miR-212 抑制肝星状细胞的激活。
DOI：
10.1038/s41419-018-1068-x
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发表时间：
2018-10-03
影响因子：
9
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Yu F;Geng W;Dong P;Huang Z;Zheng J
肝星状细胞（hepatic stellate cells，HSC）的活化是肝纤维化的关键，被认为是一个上皮-间质转化（epithelial-mesenchymal transition，EMT）过程。长链非编码RNA（longnoncodingRNA，lncRNA）的失调与人类的一系列疾病有关。LncRNA-maternally expressed gene 3（MEG 3）是一种抑癌基因，在肿瘤的发生、发展过程中起着重要作用。然而，MEG 3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，MEG 3在体内和体外肝纤维化过程中减少。MEG 3表达的恢复导致肝纤维化的抑制，α-SMA和I型胶原的减少。值得注意的是，MEG 3过表达通过EMT抑制HSC活化，与上皮标志物的增加和间充质标志物的减少相关。进一步的研究表明，Hedgehog（Hh）通路介导的EMT过程参与了MEG 3对HSC活化的影响。Smoothened（SMO）是Hh通路的成员。利用生物信息学分析，预测MEG 3和SMO蛋白之间的相互作用。RNA免疫沉淀和缺失图谱分析的结果证实了这种相互作用。此外，MEG 3被确认为microRNA-212（miR-212）的靶标。miR-212部分负责MEG 3对EMT过程的影响。有趣的是，与健康对照组相比，MEG 3在伴有肝纤维化的慢性B型肝炎（CH B）患者中也减少。MEG 3与CHB患者的纤维化分期呈负相关。总之，我们证明MEG 3通过SMO蛋白和miR-212抑制Hh介导的肝纤维化EMT过程。
Activation of hepatic stellate cells (HSCs), a pivotal event in liver fibrosis, is considered as an epithelial–mesenchymal transition (EMT) process. Deregulation of long noncoding RNAs (lncRNAs) has been reported to be involved in a series of human diseases. LncRNA-maternally expressed gene 3 (MEG3) functions as a tumor suppressor in cancers and has been shown to play a vital role in EMT process. However, the biological role of MEG3 in liver fibrosis is largely unknown. In this study, MEG3 was reduced in vivo and in vitro during liver fibrosis. Restoring of MEG3 expression led to the suppression of liver fibrosis, with a reduction in α-SMA and type I collagen. Notably, MEG3 overexpression inhibited HSC activation through EMT, associated with an increase in epithelial markers and a reduction in mesenchymal markers. Further studies showed that Hedgehog (Hh) pathway-mediated EMT process was involved in the effects of MEG3 on HSC activation. Smoothened (SMO) is a member of Hh pathway. Using bioinformatic analysis, an interaction between MEG3 and SMO protein was predicted. This interaction was confirmed by the results of RNA immunoprecipitation and deletion-mapping analysis. Furthermore, MEG3 was confirmed as a target of microRNA-212 (miR-212). miR-212 was partly responsible for the effects of MEG3 on EMT process. Interestingly, MEG3 was also reduced in chronic hepatitis B (CHB) patients with liver fibrosis when compared with healthy controls. MEG3 negatively correlated with fibrosis stage in CHB patients. In conclusion, we demonstrate that MEG3 inhibits Hh-mediated EMT process in liver fibrosis via SMO protein and miR-212.
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