microRNA-34a and microRNA-34c promote the activation of human hepatic stellate cells by targeting peroxisome proliferator-activated receptor γ
microRNA-34a and microRNA-34c promote the activation of human hepatic stellate cells by targeting peroxisome proliferator-activated receptor γ
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DOI：
10.3892/mmr.2014.2846
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发表时间：
2015-02-01
影响因子：
3.4
通讯作者：
Wang, Jinhe
中科院分区：
文献类型：
--
作者：
Li, Xiaofei;Chen, Yongxin;Wang, Jinhe
肝纤维化是几乎所有慢性肝病病例的共同结局。肝纤维化的标志是肝星状细胞（HSC）的活化。microRNA-34 a（miR-34 a）调节参与细胞周期、凋亡、分化和细胞发育的大量靶蛋白，发现其在活化的HSC和肝纤维化中上调，而在许多癌症类型中一致下调。在本研究中，miR-34 a和miR-34 c在HSC活化中的作用的可能机制进行了研究。通过生物信息学分析和荧光素酶报告基因分析，确定了5个基因为miR-34 a和miR-34 c的靶基因。其中，选择过氧化物酶体增殖物激活受体γ（PPAR γ）进行进一步研究。突变荧光素酶报告基因分析证实了PPAR γ与miR-34 a和miR-34-c的直接相互作用。Western blot分析和定量PCR结果显示，在HSC活化过程中，PPAR γ的表达与miR-34 a和miR-34 c的表达呈负相关。在活化的人HSC中，miR-34 a和miR-34 c抑制剂上调PPAR γ的表达并下调α-平滑肌肌动蛋白的表达。这些数据表明miR-34家族可能通过靶向PPAR γ参与肝纤维化的过程。
Liver fibrosis is the common outcome of almost all cases of chronic liver disease. The hallmark of liver fibrosis is the activation of hepatic stellate cells (HSCs). microRNA-34a (miR-34a), which regulates a plethora of target proteins involved in the cell cycle, apoptosis, differentiation and cellular development, is found to be upregulated in both activated HSCs and liver fibrosis, while it is consistently downregulated in numerous cancer types. In the present study, the possible mechanisms underlying the role of miR-34a and miR-34c in the activation of the HSCs was investigated. Through bioinformatics analysis and a luciferase reporter assay, five genes were identified to be the target genes of miR-34a and miR-34c. Of these, peroxisome proliferator-activated receptor gamma (PPAR gamma) was selected for further investigation. Mutation luciferase reporter assay confirmed the direct interaction of PPAR gamma and miR-34a and miR-34-c. Western blot analysis and quantitative polymerase chain reaction demonstrated that the expression of PPAR gamma was negatively correlated with the expression of miR-34a and miR-34c during the activation of HSCs. In activated human HSCs, inhibitors of miR-34a and miR-34c upregulated the expression of PPAR gamma and downregulated the expression of alpha-smooth muscle actin. These data suggested that the miR-34 family may be involved the process of liver fibrosis by targeting PPAR gamma.