Down-Regulation of Cyclin E1 Expression by MicroRNA-195 Accounts for Interferon-β-Induced Inhibition of Hepatic Stellate Cell Proliferation
Down-Regulation of Cyclin E1 Expression by MicroRNA-195 Accounts for Interferon-β-Induced Inhibition of Hepatic Stellate Cell Proliferation
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DOI：
10.1002/jcp.22598
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发表时间：
2011-10-01
影响因子：
5.6
通讯作者：
Kawada, Norifumi
中科院分区：
文献类型：
--
作者：
Sekiya, Yumiko;Ogawa, Tomohiro;Kawada, Norifumi
最近的研究表明，干扰素（ifn）在肝脏中具有独立于抗病毒作用的抗纤维化作用，尽管其详细机制在很大程度上尚不清楚。一些microrna已被报道调节肝星状细胞（hsc）的病理生理活动。我们分析了ifn在造血干细胞中的抗增殖作用，特别是关于microRNA-195 （miR-195）。我们发现miR-195在原代培养的小鼠hsc的增殖期显著下调。支持这一事实的是，ifn - β诱导miR-195表达，并通过延缓人类HSC细胞系LX-2的G1期到S期细胞周期进程来抑制细胞增殖。ifn - β下调LX-2细胞的cyclin E1，上调p21 mRNA水平。荧光素酶报告试验显示miR-195与细胞周期蛋白E1 3'UTR直接相互作用。过表达miR-195降低LX-2细胞cyclin E1 mRNA和蛋白表达水平，升高p21 mRNA和蛋白表达水平，抑制细胞增殖。此外，miR-195抑制恢复了ifn - β下调的cyclin E1水平。综上所述，ifn - β通过下调cyclin E1和上调p21抑制LX-2细胞的增殖，从而延缓细胞周期从G1期进入S期。ifn诱导的miR-195参与了这些过程。这些观察结果揭示了ifn在肝脏中抗纤维化作用的一个新的机制方面。j .细胞。中国生物医学工程学报，2011,31(2):357 - 357。(C) 2010 Wiley-Liss, Inc。
Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN-beta induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-beta down-regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3'UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-beta. In conclusion, IFN-beta inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. J. Cell. Physiol. 226: 2535-2542, 2011. (C) 2010 Wiley-Liss, Inc.