Micro-RNA Profiling Reveals a Role for miR-29 in Human and Murine Liver Fibrosis
Micro-RNA Profiling Reveals a Role for miR-29 in Human and Murine Liver Fibrosis
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DOI：
10.1002/hep.23922
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发表时间：
2011-01-01
期刊：
影响因子：
13.5
通讯作者：
Luedde, Tom
中科院分区：
文献类型：
--
作者：
Roderburg, Christoph;Urban, Gerd-Willem;Luedde, Tom
肝纤维化是由一个复杂的信号通路网络协调的，在纤维化形成过程中调节细胞外基质蛋白的沉积。MicroRNAs(MiRNAs)是一类控制多种基因翻译和转录的非编码小RNA家族。最近，miRNAs被认为对肝脏的细胞过程(如肝癌的发生)起着至关重要的调节作用。然而，它们在肝纤维化中的作用还不是很清楚。我们用基因芯片技术系统地分析了四氯化碳诱导的小鼠肝纤维化模型中miRNAs的调控，揭示了一组在肝纤维化小鼠肝脏中特异调控的miRNA。其中，miR-29家族的所有三个成员在CCl4处理的小鼠和胆管结扎小鼠的肝脏中都显著下调。在小鼠纤维化模型中miR-29成员的特异性调节与晚期肝纤维化患者肝脏中miR-29的低表达相关。此外，与健康对照组或早期纤维化患者相比，晚期肝硬变患者的血清miR-29a水平显著降低。在细胞水平上，小鼠肝星状细胞(HSCs)miR-29的下调是由转化生长因子-β(TGF-β)以及炎症信号，即脂多糖(LPS)和核因子-kappaB(NF-kappa B)介导的。此外，miR-29b在小鼠肝星状细胞中的过表达导致胶原表达下调。结论：miR-29参与了肝纤维化的调节，参与了转化生长因子-β和核因子-kappaB依赖的肝星状细胞miR-29家族成员下调和细胞外基质基因上调的信号网络。因此，它们可能是针对肝纤维化的新治疗策略的靶点，也可能成为诊断肝纤维化的生物标记物。(《肝病》2011；53：209-218)
Liver fibrosis is orchestrated by a complex network of signaling pathways regulating the deposition of extracellular matrix proteins during fibrogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. Recently, miRNAs have been suggested to crucially modulate cellular processes in the liver such as hepatocarcinogenesis. However, their role in liver fibrosis is not well understood. We systematically analyzed the regulation of miRNAs in a mouse model of carbon tetrachloride induced hepatic fibrogenesis (CCl4) by gene array analysis, which revealed a panel of miRNA that were specifically regulated in livers of mice undergoing hepatic fibrosis. Within those, all three members of the miR-29-family were significantly down-regulated in livers of CCl4-treated mice as well as in mice that underwent bile duct ligation. Specific regulation of miR-29 members in murine fibrosis models correlated with lower expression of miR-29 in livers from patients with advanced liver fibrosis. Moreover, patients with advanced liver cirrhosis showed significantly lower levels of miR-29a in their serum when compared with healthy controls or patients with early fibrosis. On a cellular level, down-regulation of miR-29 in murine hepatic stellate cells (HSCs) was mediated by transforming growth factor beta (TGF-beta) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF-kappa B). Furthermore, overexpression of miR-29b in murine HSC resulted in down-regulation of collagen expression. Conclusion: Our data indicate that miR-29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF-beta- and NF-kappa B dependent down-regulation of miR-29 family members in HSC with subsequent up-regulation of extracellular matrix genes. Thus they may represent targets for novel therapeutic strategies against hepatic fibrogenesis and also might evolve as biomarkers in the diagnosis of liver fibrosis. (HEPATOLOGY 2011;53:209-218)