MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression.
MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression.
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DOI：
10.1038/ncomms10993
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发表时间：
2016-03-22
影响因子：
16.6
通讯作者：
Jung Y
中科院分区：
文献类型：
--
作者：
Hyun J;Wang S;Kim J;Rao KM;Park SY;Chung I;Ha CS;Kim SW;Yun YH;Jung Y
Hedgehog（Hh）信号传导调节肝纤维化。microRNAs（miRNAs）介导各种细胞过程;然而，它们在肝纤维化中的作用尚不清楚。在这里，我们研究了慢性损伤的纤维化肝脏中miRNA的调控。miRNA分析显示，与玉米油处理的小鼠相比，四氯化碳（CCl 4）处理的小鼠中miR-378家族成员（miR-378 a-3 p、miR-378 b和miR-378 d）的表达下降。miR-378 a-3 p的过表达，直接靶向活化的肝星状细胞（HSC）中的Gli 3，减少Gli 3和促纤维化基因的表达，但诱导gfap，HSC的失活标志物，在CCl 4处理的肝脏。Smo通过激活核因子-κB（NF-κB）的p65亚基来阻断miR-378 a-3 p的转录表达。miR-378 a-3 p的肝脏水平与人肝细胞癌中肿瘤和非肿瘤组织中Gli 3的表达呈负相关。我们的研究结果表明，miR-378 a-3 p通过靶向Gli 3抑制HSC的活化，并且其表达受Smo依赖性NF-κB信号转导的调节，这表明miR-378 a-3 p具有治疗肝纤维化的潜力。 肝纤维化是许多肝脏疾病的致病驱动因素，因此了解其调节可能会为新疗法打开大门。在这里，作者对miRNA候选物进行了筛选，并确定miR-378通过干扰肝星状细胞中的Hedgehog信号传导来抑制小鼠的肝纤维化。
Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis. Liver fibrosis is a pathogenic driver of many liver diseases, so understanding its regulation might open the door to new therapies. Here the authors perform a screen for miRNA candidates and identify that miR-378 inhibits liver fibrosis in mice by interfering with Hedgehog signalling in hepatic stellate cells.