The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development
The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development
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microRNA-21/程序性细胞死亡蛋白4/激活蛋白1 (MiR-21/PDCD4/AP-1) 的自动调节反馈环路作为肝纤维化发展的驱动力。
DOI：
10.1074/jbc.m113.517953
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发表时间：
2013-12-27
影响因子：
4.8
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
--
作者：
Zhang, Zhengping;Zha, Yinhe;Zhang, Junfeng
肝星状细胞（HSC）的持续活化导致肝纤维化，其特征在于过量的胶原蛋白产生，并且临床上没有可用的药物。尽管取得了巨大的进展，但HSC激活的细胞活动，特别是在永存阶段的驱动力，只是部分了解。近年来发现microRNA-21（miR-21）在不同组织纤维化过程中表达上调，但其具体作用尚需进一步阐明。在本研究中，miR-21的表达在人类肝纤维化样本和小鼠肝纤维化诱导的硫代乙酰胺或四氯化碳。在活化的HSC中观察到miR-21显著增加。我们进一步发现，通过使用microRNA-21/程序性细胞死亡蛋白4/激活蛋白-1（miR-21/PDCD 4/AP-1）反馈回路，miR-21保持在恒定的高水平。用miR-21抑制剂或AP-1抑制剂破坏该环可显著抑制HSC中的纤维化活性并改善肝纤维化。相反，用针对PDCD 4的小干扰RNA（siRNA）加强该环促进HSC中的纤维化。进一步分析表明，上调的miR-21促进了HSC活化的中枢转化生长因子-（TGF-）信号通路。总之，我们认为miR-21/PDCD 4/AP-1自动调节环是肝纤维化进展的主要驱动力之一。针对这种异常激活的反馈环可能提供一种新的治疗策略，并促进抗肝纤维化药物的发现。
Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor- (TGF-) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.