Involvement of MicroRNAs in Dioxin-Induced Liver Damage in the Mouse
Involvement of MicroRNAs in Dioxin-Induced Liver Damage in the Mouse
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DOI：
10.1093/toxsci/kfr130
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发表时间：
2011-08-01
影响因子：
3.8
通讯作者：
Tohyama, Chiharu
中科院分区：
文献类型：
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作者：
Yoshioka, Wataru;Higashiyama, Wataru;Tohyama, Chiharu
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1400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的病理生理学作用在很大程度上仍然未知。因此，我们研究了miRNAs可能参与外源性化学物质的毒性反应。在这里，我们搜索了导致暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）的小鼠肝损伤的miRNA，发现miR-101 a和miR-122以时间依赖性方式被TCDD差异性下调。由于miRNA通过抑制其靶基因发挥多种作用，我们对miR-101 a的靶基因，如环氧合酶-2（考克斯-2）、zeste增强子同源物2和cFos进行了定量，发现这些基因的表达上调，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失调的miR 101 a和miR 122的表达和考克斯-2，miR 101 a的靶基因，在小鼠暴露于TCDD肝损伤中起着重要作用。
MicroRNA (miRNA) is a class of small RNA that functions as a negative regulator of gene expression. Human and mouse genomes encode over 1400 and 700 miRNAs, respectively, and most of the cellular pathways are considered to be modulated by miRNAs. However, the pathophysiological role of miRNAs is still largely unknown. 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. Because 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, 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.