Hepatitis C Virus Infection and Hepatic Stellate Cell Activation Downregulate miR-29: miR-29 Overexpression Reduces Hepatitis C Viral Abundance in Culture
Hepatitis C Virus Infection and Hepatic Stellate Cell Activation Downregulate miR-29: miR-29 Overexpression Reduces Hepatitis C Viral Abundance in Culture
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DOI：
10.1093/infdis/jir186
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发表时间：
2011-06-15
影响因子：
6.4
通讯作者：
McCaffrey, Anton P.
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, Sarmistha;Friedman, Robin C.;McCaffrey, Anton P.
方法：研究方法。TaqMan miRNA图谱确定了12个miRNA家族在慢性丙型肝炎病毒感染的人肝和未感染的对照组之间差异表达。为了识别受miRNAs影响的通路，我们开发了一种新的算法(保守靶标的通路分析)，该算法基于保守靶标的概率。这一分析表明miR-29在丙型肝炎病毒感染过程中发挥了作用。有趣的是，miR-29在大多数丙型肝炎感染患者中表达下调。MIR-29调节细胞外基质蛋白的表达。在培养中，丙型肝炎病毒感染下调miR-29，miR-29过表达降低了HCVRNA丰度。MIR-29似乎也在造血干细胞中发挥作用。肝细胞和肝星状细胞对全肝的miR-29贡献相似。原代HSCs的激活和永生化HSCs的转化生长因子-β处理均下调miR-29。MIR-29在LX-2细胞中的过表达降低了胶原蛋白的表达，并适度抑制了细胞的增殖。结论：在HSC激活过程中，丙型肝炎病毒对MIR-29的下调可能会抑制细胞外基质的合成。丙型肝炎病毒感染下调肝细胞中miR-29的表达，并可能通过降低激活的HSC中miR-29的水平来增强胶原的合成。体内用miR-29模拟物治疗可能在抑制丙型肝炎的同时减少纤维化。
Methods. TaqMan miRNA profiling identified 12 miRNA families differentially expressed between chronically HCV-infected human livers and uninfected controls. To identify pathways affected by miRNAs, we developed a new algorithm (pathway analysis of conserved targets), based on the probability of conserved targeting.Results. This analysis suggested a role for miR-29 during HCV infection. Of interest, miR-29 was downregulated in most HCV-infected patients. miR-29 regulates expression of extracellular matrix proteins. In culture, HCV infection downregulated miR-29, and miR-29 overexpression reduced HCV RNA abundance. miR-29 also appears to play a role in HSCs. Hepatocytes and HSCs contribute similar amounts of miR-29 to whole liver. Both activation of primary HSCs and TGF-beta treatment of immortalized HSCs downregulated miR-29. miR-29 overexpression in LX-2 cells decreased collagen expression and modestly decreased proliferation. miR-29 downregulation by HCV may derepress extracellular matrix synthesis during HSC activation.Conclusions. HCV infection downregulates miR-29 in hepatocytes and may potentiate collagen synthesis by reducing miR-29 levels in activated HSCs. Treatment with miR-29 mimics in vivo might inhibit HCV while reducing fibrosis.