The miR-23b/27b/24-1 Cluster Inhibits Hepatic Fibrosis by Inactivating Hepatic Stellate CellsSummary

Cellular and Molecular Gastroenterology and Hepatology

Xu Wu¹  Lin Han²  Wen-Li Cai³  Jiang-Feng Wu³  Yi-Ran Ni³  Wen-Bing Ai³  Lu Huang³  Rui Li³  Jiao-Jiao Wang⁴  Qi-Ni Cheng⁵  Meng-Yuan Liu⁵  Lan Ma⁵  Jun-Ming Li⁵  Hu Peng⁵  Hongbing Zhang⁵  Jia-Jie Liang⁵  Xue-Ping Jiang⁶  Lin-Yan Wan⁷  Yong Tan⁷  Chang-Bai Liu⁷  Quan Zhou⁷  Wen-Fang Yuan⁷  Yan-Qiong Zhang⁷  Xue Yang⁷ 

[1] Department of Oncology II, The Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, China;Department of Surgery, The Yiling Hospital of Yichang, Yichang, China;Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Yichang, China;Institute of Organ Fibrosis and Targeted Drug Delivery, The People's Hospital, China Three Gorges University, Yichang, China;Institute of Organ Fibrosis and Targeted Drug Delivery, Yichang, China;State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China;Medical College, Yichang, China;

关键词: miR-23b/27b/24-1 Cluster;    TGF-β2;    Gremlin1;    LOX;    Itgα2/5;    Hepatic Stellate Cells;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background & Aims: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-β (TGF-β) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. Methods: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. Results: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-β2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-β signaling pathway by down-regulation of TGF-β2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-β signaling increased ECM degradation. Conclusions: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.

【 授权许可】

Unknown