title: Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT.
abstract: MicroRNA-21 (miR-21) has emerged as a critical regulatory molecule and an important serum marker in hepatic fibrogenesis. The aim of the present study was to investigate the role of inhibiting miR-21 on hepatic fibrosis treatment. Serum miR-21 levels in 60 healthy individuals and 180 patients with different stages of liver cirrhosis were examined, miR-21 levels in normal or cirrhotic human liver tissues (n=10 each) were also detected. An adenoviral vector (Ad-TuD-21) carrying the sponging ToughDecoy (TuD)-RNA sequence against miR-21 was constructed to reduce miR-21 expression efficiently in vitro and in vivo Histological and immunohistological examinations were performed to evaluate the inhibitory effects and mechanism of Ad-TuD-21 delivery into carbon tetrachloride (CCl4) induced hepatic fibrosis rats by targeting extracellular signal-regulated kinase 1 (ERK1) signalling in hepatic stellate cells (HSC) and hepatocyte epithelial-mesenchymal transition (EMT). Our results revealed that enhanced miR-21 levels in cirrhotic patients were related to the severity and activity of liver cirrhosis. Ad-TuD-21 administered to liver fibrosis rats could remarkably suppress profibrotic gene expression, cause histological improvements in liver and attenuate hepatic fibrosis significantly. More importantly, after Ad-TuD-21 treatment, inhibition of both the ERK1 signalling pathway in HSC and hepatocyte EMT was confirmed, which paralleled the enhancement of miR-21 target genes-sprouty2 (SPRY2) and hepatocyte nuclear factor 4α (HNF4α)-expression in vivo These data demonstrated that miR-21 is a key regulator to promote hepatic fibrogenesis, and sponging miR-21 expression may present a novel potentially therapeutic option for hepatic fibrosis.
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Endoscopy, Shanghai Tongren Hospital, Shanghai 200336, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China Department of Endoscopy, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China linyongmd@163.com) zengxinmd1978@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China linyongmd@163.com) zengxinmd1978@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000201:enzymology; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C546082:mirn21 microRNA, rat; D048052:Mitogen-Activated Protein Kinase 3
keywords: epithelial–mesenchymal transition (EMT); extracellular signal-regulated kinase1 (ERK1) signalling pathway; hepatic fibrosis; hepatic stellate cell (HSC); hepatocyte; miR-21