miR-193a/b-3p relieves hepatic fibrosis and restrains proliferation and activation of hepatic stellate cells
miR-193a/b-3p relieves hepatic fibrosis and restrains proliferation and activation of hepatic stellate cells
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DOI：
10.1111/jcmm.14210
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Zhang, Hongjun
中科院分区：
文献类型：
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作者：
Ju, Baoling;Nie, Ying;Zhang, Hongjun
MicroRNA（miRNA）已被证实参与肝纤维化进展和肝星状细胞（HSC）的激活。在本研究中，评估了 miR-193a/b-3p 在刀豆球蛋白 A (ConA) 诱导的小鼠肝纤维化中的作用。结果显示，ConA暴露后肝组织中miR-193a/b-3p的表达下调。慢病毒介导的 miR-193a/b-3p 过度表达可减少 ConA 诱导的肝损伤，这一点通过降低 ALT 和 AST 水平来证明。此外，通过抑制胶原沉积、减少结蛋白和增殖细胞核抗原（PCNA）表达以及减少肝组织中羟脯氨酸、转化生长因子-β1（TGF-β1）和激活素A的含量，上调miR-193a/b-3来抑制ConA诱导的肝纤维化。此外，miR-193a/b-3p模拟物通过诱导LX-2细胞凋亡并降低细胞周期相关蛋白Cyclin D1、Cyclin E1、p-Rb和CAPRIN1的水平来抑制人HSC LX-2的增殖。最后，miR-193a/b-3p模拟物通过抑制COL1A1和β-SMA表达并抑制TGF-β/Smad2/3信号通路的激活来逆转TGF-β1和激活素A介导的LX-2细胞激活。 CAPRIN1和TGF-β2被证明是miR-193a/b-3p的直接靶基因。我们得出的结论是，miR-193a/b-3p 过表达通过抑制 HSC 的增殖和活化来减轻肝纤维化。我们的数据表明miR-193a-3p和miR-193b-3p可能是肝纤维化的新治疗靶点。
MicroRNAs (miRNAs) have been confirmed to participate in liver fibrosis progression and activation of hepatic stellate cells (HSCs). In this study, the role of miR-193a/b-3p in concanavalin A (ConA)-induced liver fibrosis in mice was evaluated. According to the results, the expression of miR-193a/b-3p was down-regulated in liver tissues after exposure to ConA. Lentivirus-mediated overexpression of miR-193a/b-3p reduced ConA-induced liver injury as demonstrated by decreasing ALT and AST levels. Moreover, ConA-induced liver fibrosis was restrained by the up-regulation of miR-193a/b-3 through inhibiting collagen deposition, decreasing desmin and proliferating cell nuclear antigen (PCNA) expression and lessening the content of hydroxyproline, transforming growth factor-beta 1 (TGF-beta 1) and activin A in liver tissues. Furthermore, miR-193a/b-3p mimics suppressed the proliferation of human HSCs LX-2 via inducing the apoptosis of LX-2 cells and lowering the levels of cell cycle-related proteins Cyclin D1, Cyclin E1, p-Rb and CAPRIN1. Finally, TGF-beta 1 and activin A-mediated activation of LX-2 cells was reversed by miR-193a/b-3p mimics via repressing COL1A1 and beta-SMA expression, and restraining the activation of TGF-beta/Smad2/3 signalling pathway. CAPRIN1 and TGF-beta 2 were demonstrated to be the direct target genes of miR-193a/b-3p. We conclude that miR-193a/b-3p overexpression attenuates liver fibrosis through suppressing the proliferation and activation of HSCs. Our data suggest that miR-193a-3p and miR-193b-3p may be new therapeutic targets for liver fibrosis.