title: 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.
abstract: 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-β (TGF-β) 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.
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China and.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yinhe
authors.initials: Y
authors.lastname: Zha
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.forename: Zhongfei
authors.initials: Z
authors.lastname: Gao
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Zang
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013853:Thioacetamide / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D013853:Thioacetamide; D002251:Carbon Tetrachloride
keywords: Fibrosis; Hepatic Stellate Cells; Liver Injury; MicroRNA; Transforming Growth Factor β (TGFβ)