MicroRNA-489-3p Represses Hepatic Stellate Cells Activation by Negatively Regulating the JAG1/Notch3 Signaling Pathway
MicroRNA-489-3p Represses Hepatic Stellate Cells Activation by Negatively Regulating the JAG1/Notch3 Signaling Pathway
复制标题
MicroRNA-489-3p 通过负向调节 JAG1/Notch3 信号通路抑制肝星状细胞活化
DOI：
10.1007/s10620-020-06174-w
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发表时间：
2020-03-07
影响因子：
3.1
通讯作者：
Wang, Hongling
中科院分区：
文献类型：
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作者：
Li, Juanjuan;Dong, Shouquan;Wang, Hongling
背景肝星状细胞（hepatic stellate cells，HSC）向肌成纤维细胞转化是肝纤维化发生的关键环节。最近的研究表明，microRNAs（miRNAs）在HSC的转化过程中起着关键作用。方法以四氯化碳（CCl 4）处理的大鼠为体内模型，以转化生长因子-β 1（TGF-β1）处理的HSC细胞系LX-2和HSC-T6为体外模型，检测miR-489- 3 p和JAG 1在肝纤维化中的表达水平。通过用miR-489- 3 p模拟物或si-JAG 1转染LX-2细胞来影响促纤维化标志物的表达。采用双荧光素酶报告基因技术研究JAG 1与miR-489- 3 p的相互作用。结果在肝纤维化模型中，miR-489- 3 p表达明显降低，而JAG 1表达明显升高。miR-489- 3 p过表达可降低促纤维化标志物的表达和TGF-β1诱导的LX-2细胞活化。此外，miR-489- 3 p通过与其3 ′端非翻译区相互作用，降低LX-2细胞中Jaged canonical Notch ligand 1（JAG 1）的表达。由于JAG 1是Notch配体，通过miR-489- 3 p减少JAG 1抑制Notch信号通路。结论miR-489- 3 p可通过抑制JAG 1/Notch 3信号通路抑制HSC活化。
BackgroundThe transformation of hepatic stellate cells (HSCs) into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis. Recent studies have shown that microRNAs (miRNAs) play a critical role in the transformation of HSCs. However, the function of miR-489-3p in liver fibrosis remains unclear.MethodsHere, we detected the levels of miR-489-3p and jagged canonical Notch ligand 1 (JAG1) in liver fibrosis by using CCl4-treated rats as an in vivo model and transforming growth factor-beta 1 (TGF-β1)-treated HSC cell lines LX-2 and HSC-T6 as in vitro models. The expression of profibrotic markers was affected by transfecting LX-2 cells with either miR-489-3p mimic or si-JAG1. A dual-luciferase reporter assay was carried out to study the interaction of JAG1 with miR-489-3p.ResultsWe found that miR-489-3p was remarkably decreased while JAG1 was increased in liver fibrosis models both in vivo and in vitro. Overexpression of miR-489-3p reduced the expression of profibrotic markers and the activation of LX-2 cells induced by TGF-β1. Moreover, miR-489-3p decreased the expression of jagged canonical Notch ligand 1 (JAG1) in LX-2 cells by interacting with its 3ʹ-UTR. As JAG1 is a Notch ligand, decreased JAG1 by miR-489-3p inhibited the Notch signaling pathway. Moreover, the downregulation of JAG1 inhibited the expression of fibrotic markers.ConclusionOur results indicate that miR-489-3p can inhibit HSC activation by inhibiting the JAG1/Notch3 signaling pathway.