MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4
MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4
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DOI：
10.1016/j.cellsig.2012.06.003
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发表时间：
2012-10-01
影响因子：
4.8
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
He, Yong;Huang, Cheng;Li, Jun
肝星状细胞（HSC）的活化在肝纤维化的发生发展中起着关键作用。转化生长因子β 1（Transforming growth factor-beta 1，TGF-β 1）被认为是激活HSC的主要刺激因子。最近已经证明microRNA（miRNAs）调节细胞增殖、分化和凋亡。miRNA的参与及其在TGF-β 1诱导的HSC活化中的作用在很大程度上仍然未知。我们的研究通过一步实时定量PCR发现，miR-146 a在HSC中的表达在TGF-β 1刺激下呈剂量依赖性下调。此外，我们试图检查miR-146 a是否在CCl 4诱导的大鼠肝纤维化中变得失调。我们的研究表明，miR-146 a在肝纤维化组织中下调。此外，与对照组相比，转染miR-146 a模拟物的HSC表现出TGF-β 1诱导的α-平滑肌肌动蛋白（α-SMA）表达的减弱。此外，miR-146 a的过表达抑制TGF-β 1诱导的HSC增殖，并增加HSC凋亡。生物信息学分析预测SMAD 4是miR-146 a的潜在靶点。在TGF-β 1处理的HSC中，miR-146 a过表达不降低靶mRNA水平，但显著降低靶蛋白表达。这些结果表明，miR-146 a可能作为一种新型调节因子，通过靶向SMAD 4调节TGF-β 1诱导期间的HSC活化。(c)2012 Elsevier Inc. All rights reserved.
Activation of hepatic stellate cells (HSC) plays a pivotal role in the development of hepatic fibrosis. Transforming growth factor-beta 1 (TGF-beta 1) is considered to be the main stimuli factor responsible for the activation of HSC. MicroRNAs (miRNAs) have recently been shown to regulate cell proliferation, differentiation, and apoptosis. The involvement of miRNAs and their roles in TGF-beta 1-induced HSC activation remains largely unknown. Our study found that the expression of miR-146a was downregulated in HSC in response to TGF-beta 1 stimulation in dose-dependent manner by one-step real-time quantitative PCR. Moreover, we sought to examine whether miR-146a became dysregulated in CCI4-induced hepatic fibrosis in rats. Our study revealed that miR-146a was downregulated in liver fibrotic tissues. In addition, The HSC transfected with miR-146a mimics exhibited attendated TGF-beta 1-induced a-smooth muscle actin (alpha-SMA) expression compared with the control. Furthermore, overexpression of miR-146a suppressed TGF-beta 1-induced HSC proliferation, and increased HSC apoptosis. Bioinformatics analyses predict that SMAD4 is the potential target of miR-146a. MiR-146a overexpression in TGF-beta 1-treated HSC did not decrease target mRNA levels, but significantly reduced target protein expression. These results suggested that miR-146a may function as a novel regulator to modulate HSC activation during TGF-beta 1 induction by targeting SMAD4. (c) 2012 Elsevier Inc. All rights reserved.