Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis.
Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis.
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DOI：
10.1002/hep.25613
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发表时间：
2012-07
期刊：
影响因子：
13.5
通讯作者：
Schrum, Laura W.
中科院分区：
文献类型：
--
作者：
Lakner, Ashley M.;Steuerwald, Nury M.;Walling, Tracy L.;Ghosh, Sriparna;Li, Ting;McKillop, Iain H.;Russo, Mark W.;Bonkovsky, Herbert L.;Schrum, Laura W.
肝星状细胞（HSC）激活是肝纤维化发生和发展的关键事件，也是转化生长因子β (tgf - β)驱动的胶原沉积的主要因素。microRNAs （miRs）是一种调节mRNA和蛋白质表达的小非编码rna，已成为慢性肝病的关键调控分子。我们研究了静止和激活hsc中差异表达的miRs，以确定纤维化tgf - β信号传导的新调控因子。对静止和激活的大鼠造血干细胞进行miR芯片分析。miR-17-92簇的成员（19a, 19b, 92a）在活化的hsc中显著下调。由于miR 19b在集群成员中表现出最高的折叠变化，因此用miR 19b模拟或阴性对照转染活化的HSC，并评估TGFβ信号传导和HSC活化。检测miR 19b在纤维化大鼠和人肝脏标本中的表达。miR 19b模拟负调控TGFβ信号成分，表现为TGFβ受体II （TGFβ rii）和SMAD3表达降低。荧光素酶报告基因试验验证了miR 19b与TGFβRII的3'UTR结合的计算预测。miR - 19b对tgf - β信号传导的抑制作用通过I型胶原表达的降低和tgf - β诱导的α1(I)和α2(I)前胶原mrna的表达被证实。miR 19b使活化的HSC表型钝化，αSMA表达降低。此外，与正常肝脏相比，miR 19b在纤维化大鼠肝脏中的表达明显降低；同样，与正常人类肝脏相比，miR 19b在纤维化肝脏中的表达明显下调。miR 19b是造血干细胞中TGFβ信号的一种新型调节剂，提示肝纤维化的潜在治疗方法。
Hepatic stellate cell (HSC) activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition driven by transforming growth factor beta (TGFβ). microRNAs (miRs), small non-coding RNAs modulating mRNA and protein expression, have emerged as key regulatory molecules in chronic liver disease. We investigated differentially expressed miRs in quiescent and activated HSCs to identify novel regulators of profibrotic TGFβ signaling. miR microarray analysis was performed on quiescent and activated rat HSCs. Members of the miR-17-92 cluster (19a, 19b, 92a) were significantly down-regulated in activated HSCs. Since miR 19b showed the highest fold-change of the cluster members, activated HSCs were transfected with miR 19b mimic or negative control and TGFβ signaling and HSC activation assessed. miR 19b expression was determined in fibrotic rat and human liver specimens. miR 19b mimic negatively regulated TGFβ signaling components demonstrated by decreased TGFβ receptor II (TGFβRII) and SMAD3 expression. Computational prediction of miR 19b binding to the 3’UTR of TGFβRII was validated by luciferase reporter assay. Inhibition of TGFβ signaling by miR 19b was confirmed by decreased expression of type I collagen and by blocking TGFβ-induced expression of α1(I) and α2(I) procollagen mRNAs. miR 19b blunted the activated HSC phenotype by morphological assessment and decreased αSMA expression. Additionally, miR 19b expression was markedly diminished in fibrotic rat liver compared to normal liver; similarly, miR 19b expression was markedly down-regulated in fibrotic compared to normal human livers. miR 19b is a novel regulator of TGFβ signaling in HSCs suggesting a potential therapeutic approach for hepatic fibrosis.
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影响因子：
6.2
作者：
Chung, GG;Yoon, HH;Burtness, BA
通讯作者：
Burtness, BA
DOI：
10.1073/pnas.96.22.12719
发表时间：
1999-10-26
影响因子：
11.1
作者：
George, J;Roulot, D;Bissell, DM
通讯作者：
Bissell, DM
影响因子：
4.3
作者：
Chen, Xian-Ming
通讯作者：
Chen, Xian-Ming
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko
影响因子：
8
作者：
Kanzler, S;Meyer, E;Blessing, M
通讯作者：
Blessing, M