Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans
Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans
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DOI：
10.1038/labinvest.2010.126
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发表时间：
2010-12-01
影响因子：
5
通讯作者：
McCaffrey, Anton P.
中科院分区：
文献类型：
--
作者：
Marquez, Rebecca T.;Bandyopadhyay, Sarmistha;McCaffrey, Anton P.
microRNAs（miRNAs）是一类调节基因表达的小分子RNA。先前的研究表明丙型肝炎病毒（HCV）和宿主miRNA之间存在相互作用。我们测量了HCV感染的人肝活检组织中miR-122和miR-21的水平，并将其与临床患者数据相关联。miR-122是HCV体外复制所必需的，而miR-21参与细胞增殖和肿瘤发生。我们发现miR-21表达与病毒载量、纤维化和血清肝转氨酶水平相关。miR-122表达与纤维化、肝转氨酶水平和患者年龄呈负相关。在用HCV J6/JFH感染性克隆感染培养的细胞时，miR-21被诱导接近两倍，并且miR-122被下调，从而建立了与HCV的联系。为了进一步研究纤维化与miR-21和miR-122水平之间的关系，我们在小鼠四氯化碳纤维化模型中测量了它们的表达水平。与HCV感染患者样本一样，纤维化分期与miR-21水平呈正相关，与miR-122水平呈负相关。转化生长因子β（TGF-β）是纤维形成的关键介质。我们将SMAD 7确定为一种新的miR-21靶点。SMAD 7是TGF-β信号传导的负调节因子，其表达由TGF-β诱导。为了证实miR-21和TGF-β信号通路之间的关系，我们测量了miR-21对TGF-β响应报告基因的影响。我们发现miR-21增强了TGF-β信号传导，进一步支持了miR-21与纤维化之间的关系。我们提出了一种模型，其中miR-21靶向SMAD 7可以增加TGF-β信号传导，导致纤维化增加。实验室调查（2010）90，1727-1736; doi：10.1038/labinvest.2010.126;在线发表2010年7月12日
MicroRNAs (miRNAs) are small RNAs that regulate gene expression pathways. Previous studies have shown interactions between hepatitis C virus (HCV) and host miRNAs. We measured miR-122 and miR-21 levels in HCV-infected human liver biopsies relative to uninfected human livers and correlated these with clinical patient data. miR-122 is required for HCV replication in vitro, and miR-21 is involved in cellular proliferation and tumorigenesis. We found that miR-21 expression correlated with viral load, fibrosis and serum liver transaminase levels. miR-122 expression inversely correlated with fibrosis, liver transaminase levels and patient age. miR-21 was induced similar to twofold, and miR-122 was downregulated on infection of cultured cells with the HCV J6/JFH infectious clone, thus establishing a link to HCV. To further examine the relationship between fibrosis and the levels of miR-21 and miR-122, we measured their expression levels in a mouse carbon tetrachloride fibrosis model. As in the HCV-infected patient samples, fibrotic stage positively correlated with miR-21 and negatively correlated with miR-122 levels. Transforming growth factor beta (TGF-beta) is a critical mediator of fibrogenesis. We identified SMAD7 as a novel miR-21 target. SMAD7 is a negative regulator of TGF-beta signaling, and its expression is induced by TGF-beta. To confirm the relationship between miR-21 and the TGF-beta signaling pathway, we measured the effect of miR-21 on a TGF-beta-responsive reporter. We found that miR-21 enhanced TGF-beta signaling, further supporting a relationship between miR-21 and fibrosis. We suggest a model in which miR-21 targeting of SMAD7 could increase TGF-beta signaling, leading to increased fibrogenesis. Laboratory Investigation (2010) 90, 1727-1736; doi:10.1038/labinvest.2010.126; published online 12 July 2010