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Are miRNAs involved in responses to environmental chemicals?

miRNA 是否参与对环境化学物质的反应？

基本信息

批准号：
21710066
负责人：
YOSHIOKA Wataru
金额：
$ 2.91万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21710066/
关键词：
環境汚染化学物質 miRNA COX-2 ダイオキシンマイクロRNA マウス肝臓

项目摘要

MicroRNA (miRNA) is a class of small RNA that functions as a negative regulator of gene expression. Human and mouse genomes encode over 1,400 and 700 miRNAs, respectively, and most of the cellular pathways are considered to be modulated by miRNAs. However, it is still largely unknown about the pathophysiological role of miRNAs. Thus, we investigated the possible involvement of miRNAs in the toxic responses to xenobiotic chemicals.Here, we searched for miRNAs responsible for inducing liver damage in mice exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and found that miR-101a and miR-122 are differentially downregulated by TCDD in a time-dependent manner. Since miRNA exerts multiple actions by repressing its target genes, we quantified the target genes of miR-101a, such as cyclooxygenase-2 (COX-2), enhancer of zeste homolog 2 (EZH2), and cFos, and found the upregulation of these genes, which suggests that miR-101a downregulates the expressions of these genes in the mouse liver. A COX-2 selective inhibitor, NS-398, suppressed the onset of TCDD-induced liver damage. In conclusion, this study demonstrated that TCDD dysregulates the expression of miR101a and miR122, and that COX-2, a target gene of miR101a, plays a significant role in liver damage in mice exposed to TCDD.

MicroRNA（miRNA）是一类小分子RNA，在基因表达中起负调控作用。人类和小鼠基因组分别编码超过1，400和700种miRNA，并且大多数细胞途径被认为是由miRNA调节的。然而，miRNAs的病理生理作用在很大程度上仍然未知。因此，我们研究了miRNAs在外源性化学物质毒性反应中的可能参与，在此，我们寻找了导致暴露于2，3，7，8-四氯二苯并-对-二恶英（TCDD）的小鼠肝损伤的miRNAs，发现miR-101 a和miR-122以时间依赖的方式被TCDD差异下调。由于miRNA通过抑制其靶基因发挥多种作用，我们定量了miR-101 a的靶基因，如环氧合酶-2（考克斯-2）、zeste同源物增强子2（EZH 2）和cFos，发现这些基因的上调，这表明miR-101 a下调了这些基因在小鼠肝脏中的表达。考克斯-2选择性抑制剂NS-398可抑制TCDD诱导的肝损伤。总之，本研究表明，TCDD异常调节miR 101 a和miR 122的表达，并且miR 101 a的靶基因考克斯-2在暴露于TCDD的小鼠的肝损伤中起重要作用。