title: Involvement of microRNAs in dioxin-induced liver damage in the mouse.
abstract: 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.
authors: Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Wataru
authors: W
authors: Yoshioka
authors: Wataru
authors: W
authors: Higashiyama
authors: Chiharu
authors: C
authors: Tohyama