Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver
Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver
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DOI：
10.1016/j.taap.2015.07.004
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发表时间：
2015-10-01
影响因子：
3.8
通讯作者：
Pustylnyak, Vladimir O.
中科院分区：
文献类型：
--
作者：
Kazantseva, Yuliya A.;Yarushkin, Andrei A.;Pustylnyak, Vladimir O.
MiR-122是肝脏中主要的microRNA，占肝脏miRNA总数的70%以上。研究表明，miR-122与肝脏疾病相关，包括肝细胞癌。Mir-122是一种具有自身启动子的基因间miRNA。Pri-miR-122的表达受肝脏富集转录因子调控，主要受HNF4 α调控，其通过与特定DR1位点的相互作用介导表达。研究表明，苯巴比妥介导的异种核受体组成型雄甾受体（CAR）的激活与肝脏中miR-122的降低有关。在本研究中，我们研究了HNF4 α - car串导对小鼠肝脏中miR-122水平和促生信号传导的调节。miR-122水平被1,4-双[2-（3,5-二氯吡啶氧基）]苯（TCPOBOP）治疗显著抑制，TCPOBOP是小鼠CAR的激动剂。ChIP实验表明，tcpobop激活的CAR通过与HNF4 α竞争结合pri-miR-122启动子中的DR1位点来抑制HNF4a的转激活。这种转录因子替代与miR-122下调密切相关。此外，CAR激活产生的miR-122水平的降低伴随着E2f1 mRNA和细胞蛋白水平的增加及其在靶cMyc基因启动子上的积累。靶cMyc基因启动子上E2f1积累的增加伴随着cMyc水平和转录活性的增加。因此，我们的研究结果为CAR激活通过抑制HNF4 α转录活性降低miR-122水平并间接调节促生蛋白cMyc的结论提供了证据。HNF4 α - car串扰可能为了解肝脏疾病和开发更有效的治疗方法提供新的机会，从而更好地进行药物治疗。(C) 2015爱思唯尔公司版权所有。
MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4 alpha, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4 alpha-CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4a transactivation by competing with HNF4 alpha for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4 alpha transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4 alpha-CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. (C) 2015 Elsevier Inc. All rights reserved.