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.
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GABAB receptor-mediated hypertension via hyperpolarization of solitary tract nucleus neurons that receive and integrate baroreceptor afferent inputs. See pp. 1417-1434 for further details. Image kindly provided by Omar Logue
Research Article|
July 07 2016
Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT
Kaiming Wu;
Kaiming Wu
1
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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Changhong Ye;
Changhong Ye
1
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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Lin Lin;
Lin Lin
1
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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Yimin Chu;
Yimin Chu
†Department of Endoscopy, Shanghai Tongren Hospital, Shanghai 200336, China
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Meng Ji;
Meng Ji
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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Weiping Dai;
Weiping Dai
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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Xin Zeng;
*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
Correspondence: Yong Lin (email [email protected]) or Xin Zeng (email [email protected]).
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Yong Lin
*Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
Correspondence: Yong Lin (email [email protected]) or Xin Zeng (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 13 2016
Revision Received:
May 24 2016
Accepted:
May 25 2016
Accepted Manuscript online:
May 25 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (16): 1469–1480.
Article history
Received:
May 13 2016
Revision Received:
May 24 2016
Accepted:
May 25 2016
Accepted Manuscript online:
May 25 2016
Citation
Kaiming Wu, Changhong Ye, Lin Lin, Yimin Chu, Meng Ji, Weiping Dai, Xin Zeng, Yong Lin; Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT. Clin Sci (Lond) 1 August 2016; 130 (16): 1469–1480. doi: https://doi.org/10.1042/CS20160334
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