Frontiers in Cell and Developmental Biology (Jun 2020)
MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression
- Qi Wang,
- Qi Wang,
- Qi Wang,
- Qi Wang,
- Qi Wang,
- Song Wei,
- Song Wei,
- Song Wei,
- Song Wei,
- Song Wei,
- Haoming Zhou,
- Haoming Zhou,
- Haoming Zhou,
- Haoming Zhou,
- Lei Li,
- Lei Li,
- Lei Li,
- Lei Li,
- Shun Zhou,
- Shun Zhou,
- Shun Zhou,
- Shun Zhou,
- Chengyu Shi,
- Chengyu Shi,
- Chengyu Shi,
- Chengyu Shi,
- Yong Shi,
- Yong Shi,
- Yong Shi,
- Yong Shi,
- Jiannan Qiu,
- Jiannan Qiu,
- Jiannan Qiu,
- Jiannan Qiu,
- Ling Lu,
- Ling Lu,
- Ling Lu,
- Ling Lu,
- Ling Lu,
- Ling Lu,
- Ling Lu
Affiliations
- Qi Wang
- School of Medicine, Southeast University, Nanjing, China
- Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Qi Wang
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Qi Wang
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Qi Wang
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Song Wei
- School of Medicine, Southeast University, Nanjing, China
- Song Wei
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Song Wei
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Song Wei
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Song Wei
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Haoming Zhou
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Haoming Zhou
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Haoming Zhou
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Lei Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Lei Li
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Lei Li
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Lei Li
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Shun Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Shun Zhou
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Shun Zhou
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Shun Zhou
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Chengyu Shi
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Chengyu Shi
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Chengyu Shi
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Chengyu Shi
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Yong Shi
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Yong Shi
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Yong Shi
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Yong Shi
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Jiannan Qiu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiannan Qiu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Jiannan Qiu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Jiannan Qiu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Ling Lu
- School of Medicine, Southeast University, Nanjing, China
- Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Ling Lu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Ling Lu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Ling Lu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Ling Lu
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Ling Lu
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
- DOI
- https://doi.org/10.3389/fcell.2020.00513
- Journal volume & issue
-
Vol. 8
Abstract
Liver fibrosis is a major endpoint of patients with chronic liver diseases. The molecular mechanisms behind liver fibrosis remain largely unknown. Many studies have indicated the role of microRNA (miRNA) in hepatic tumorigenesis. But the role of miRNA in liver fibrosis is little known. Activated hepatic stellate cells (HSCs) can secret extracellular matrix proteins (ECM) and are the major contributors to liver fibrosis/cirrhosis. Here, a microarray assay of quiescent and transforming growth factor β1 (TGF-β1) activated HSCs indicated that miR-98 might play a crucial role in liver fibrosis. We found that miR-98 was significantly downregulated in activated HSCs. miR-98 overexpression inhibited HSCs activation. Furthermore, we hypothesized that miR-98 regulated hepatic leukemia factor (HLF) expression by binding to the 3′ UTR of its mRNA directly, as evidenced by luciferase reporter assay. HLF overexpression increased HSCs activation by inducing hypoxia inducible factor-1 alpha (HIF-1α) expression, resulting in the activation of TGF-β/Smad2/3 signaling pathway. Besides, low expression of miR-98 was also found in liver tissues from various fibrotic murine models, including carbon tetrachloride (CCl4), bile duct ligation (BDL), and high-fat diet (HFD)-induced liver fibrosis. miR-98 overexpression in vivo by ago-miR-98 injection could attenuate CCl4-, BDL-, and HFD-induced murine hepatic fibrosis. Meanwhile, miR-98 overexpression suppressed HLF expression and reduced fibrosis marker expression. Collectively, our study demonstrates that miR-98 suppress HSCs activation by targeting HLF directly and interacting with HIF-1α/TGF-β/Smad2/3 signaling pathway, which may be an effective therapeutic target for liver fibrosis.
Keywords