MiRNA-Based Regulation of Hemostatic Factors through Hepatic Nuclear Factor-4 Alpha.
MiRNA-Based Regulation of Hemostatic Factors through Hepatic Nuclear Factor-4 Alpha.
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DOI：
10.1371/journal.pone.0154751
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
González-Conejero R
中科院分区：
文献类型：
--
作者：
Salloum-Asfar S;Arroyo AB;Teruel-Montoya R;García-Barberá N;Roldán V;Vicente V;Martínez C;González-Conejero R
miRNAs已被报道为几种止血因子的顺式作用元件，然而，它们作为转录因子介导的反式作用元件的机制知之甚少，并且可能具有重要作用。HNF 4 α在多种肝凝血基因的调控中具有直接而重要的作用。先前的体外研究已经证明miR-24- 3 p和miR-34 a-5 p调节HNF 4A的表达。本研究旨在探讨miR-24和miR-34 a通过HNF 4A影响凝血的分子机制。在HepG 2细胞中转染miR-24和miR-34 a不仅降低HNF 4A，而且降低F10、F12、SERPINC 1、PROS 1、PROC和PROZ转录物水平。在人肝脏样本（N = 104）中观察到HNF 4A水平与几种止血因子（F5、F8、F9、F11、F12、SERPINC 1、PROC和PROS 1）之间存在正相关和显著相关性。然而，这些肝脏样本的低（第10）和高（第90）水平的miR-24和miR-34 a水平与HNF 4A和几乎所有止血因子表达水平呈负相关。这些结果表明，miR-24和miR-34 a可能是调节几种止血因子的两个间接元件。此外，miRNA表达谱的变化至少可以部分证明HNF 4A表达水平及其下游凝血靶点的变化。
MiRNAs have been reported as CIS-acting elements of several hemostatic factors, however, their mechanism as TRANS-acting elements mediated by a transcription factor is little known and could have important effects. HNF4α has a direct and important role in the regulation of multiple hepatic coagulation genes. Previous in vitro studies have demonstrated that miR-24-3p and miR-34a-5p regulate HNF4A expression. Here we aimed to investigate the molecular mechanisms of miR-24 and miR-34a on coagulation through HNF4A. Transfections with miR-24 and miR-34a in HepG2 cells decreased not only HNF4A but also F10, F12, SERPINC1, PROS1, PROC, and PROZ transcripts levels. Positive and significant correlations were observed between levels of HNF4A and several hemostatic factors (F5, F8, F9, F11, F12, SERPINC1, PROC, and PROS1) in human liver samples (N = 104). However, miR-24 and miR-34a levels of the low (10th) and high (90th) percentiles of those liver samples were inversely correlated with HNF4A and almost all hemostatic factors expression levels. These outcomes suggest that miR-24 and miR-34a might be two indirect elements of regulation of several hemostatic factors. Additionally, variations in miRNA expression profiles could justify, at least in part, changes in HNF4A expression levels and its downstream targets of coagulation.