Regulation of coagulation factor XI expression by microRNAs in the human liver.
Regulation of coagulation factor XI expression by microRNAs in the human liver.
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DOI：
10.1371/journal.pone.0111713
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Martínez C
中科院分区：
文献类型：
--
作者：
Salloum-Asfar S;Teruel-Montoya R;Arroyo AB;García-Barberá N;Chaudhry A;Schuetz E;Luengo-Gil G;Vicente V;González-Conejero R;Martínez C
高水平的凝血因子XI(FXI)会增加血栓栓塞性疾病的风险。然而，调控FXI表达的遗传和环境因素在很大程度上仍不清楚。本研究的目的是评价microRNAs(MiRNAs)对人肝脏FXI的调节作用。在计算机预测中，产生了四个可能调节FXI表达的miRNA候选者。将miR-181a-5p、miR-23a-3p、miR-16-5p和miR-195-5p分别导入HepG2细胞。我们使用未被预测与F11结合的mir-494作为阴性对照。仅miR-181a-5p能显著降低FXI蛋白和F11mRNA水平。此外，将miR-181a-5p抑制剂导入PLC/PRF/5肝细胞后，F11基因的表达水平和细胞外FXI水平均升高。在DICER基因缺陷的人结肠癌细胞(HCT-DK)中的荧光素酶分析表明，miR-181a-5p与F11的3‘非翻译区之间存在直接相互作用。此外，在114例健康肝脏中，F11mRNA水平与miR-181a-5p水平呈显著负相关，而与miR-494无相关性。本研究证明，FXI的表达直接受人体肝脏中一种特定的miRNA，miR-181a-5p调节。未来的研究是必要的，以进一步研究miRNA失调在涉及FXI的病理中的潜在后果。
High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR-23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3′untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI.
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