AhR is negatively regulated by miR-203 in response to TCDD or BaP treatment
AhR is negatively regulated by miR-203 in response to TCDD or BaP treatment
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DOI：
10.1039/c3tx50083g
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发表时间：
2014-02
影响因子：
2.1
通讯作者：
Daochuan Li;Caixia Liu;Hao-cheng Yu;Xiao-wen Zeng;X. Xing;Li-ping Chen;Chen Gao;Zhengbao Zhang;Yong-mei Xiao;H. Duan;Yu-xin Zheng;Qing Wang;Wen Chen
中科院分区：
文献类型：
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作者：
Daochuan Li;Caixia Liu;Hao-cheng Yu;Xiao-wen Zeng;X. Xing;Li-ping Chen;Chen Gao;Zhengbao Zhang;Yong-mei Xiao;H. Duan;Yu-xin Zheng;Qing Wang;Wen Chen
芳香烃受体（aryl hydrocarbon receptor，AhR）是一种重要的核受体，介导环境刺激的生物学效应。然而，AhR在这一过程中的调控机制尚不清楚。在这项研究中，我们试图确定哪些microRNAs（miRNAs）特异性地修饰A549和HepG 2细胞中AhR的表达。通过生物信息学分析预测miR-203靶向AhR。我们进行了荧光素酶报告基因分析，发现miR-203特异性结合AhR mRNA的3′-UTR区域，导致AhR在mRNA和蛋白水平上的表达受到抑制。当TCDD或BaP暴露时，miR-203的表达可被诱导，并导致AhR表达降低。miR-203在A549和HepG 2细胞中的异位表达减弱了TCDD诱导的AhR激活，随后抑制了其下游调控基因，包括细胞色素P450 1A 1、1A 2（CYP 1A 1、CYP 1A 2）和NADPH脱氢酶1（NQO 1）。此外，miR-203的过表达影响TCDD诱导的CYP 1A 1的诱导酶活性和BaP诱导的细胞毒性。总之，我们确定了一种新的miRNA，负调控AhR的表达，表明表观遗传修饰在环境化学物质的代谢活化中起着至关重要的作用。
The aryl hydrocarbon receptor (AhR) is an important nuclear receptor and mediates the biological consequences in response to environmental stimuli. However, the mechanism of AhR regulation in this process is still unclear. In this study, we attempt to identify which microRNAs (miRNAs) specifically modify the expression of AhR in A549 and HepG2 cells. miR-203 was predicted to target AhR by bioinformatic analysis. We performed a luciferase reporter assay and found miR-203 specifically binding to the mRNA 3′-UTR region of AhR, leading to the suppression of the expression of AhR at both the mRNA and protein levels. When exposed to TCDD or BaP, the expression of miR-203 could be induced and resulted in a reduction of AhR expression. The ectopic expression of miR-203 in A549 and HepG2 cells attenuated the activation of AhR induced by TCDD and subsequently suppressed its downstream regulated genes including cytochrome P450 1A1, 1A2 (CYP1A1, CYP1A2), and NADPH dehydrogenase 1 (NQO1). Moreover, overexpression of miR-203 affects the inducible enzyme activity of CYP1A1 by TCDD induction and the cytotoxicity induced by BaP. Taken together, we identify a novel miRNA that negatively regulates the expression of AhR, demonstrating that epigenetic modifications play a critical role in the metabolic activation of environmental chemicals.