MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression
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 hep...
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Frontiers Media S.A.
2020-06-01
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00513/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qi Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T20:25:40Z |
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| language | English |
| last_indexed | 2024-12-11T20:25:40Z |
| publishDate | 2020-06-01 |
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| spelling | doaj.art-a259beccdee446cdadb271a2cbbfb0be2022-12-22T00:51:57ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-06-01810.3389/fcell.2020.00513549132MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF ExpressionQi Wang0Qi Wang1Qi Wang2Qi Wang3Qi Wang4Song Wei5Song Wei6Song Wei7Song Wei8Song Wei9Haoming Zhou10Haoming Zhou11Haoming Zhou12Haoming Zhou13Lei Li14Lei Li15Lei Li16Lei Li17Shun Zhou18Shun Zhou19Shun Zhou20Shun Zhou21Chengyu Shi22Chengyu Shi23Chengyu Shi24Chengyu Shi25Yong Shi26Yong Shi27Yong Shi28Yong Shi29Jiannan Qiu30Jiannan Qiu31Jiannan Qiu32Jiannan Qiu33Ling Lu34Ling Lu35Ling Lu36Ling Lu37Ling Lu38Ling Lu39Ling Lu40School of Medicine, Southeast University, Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaSchool of Medicine, Southeast University, Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaSchool of Medicine, Southeast University, Nanjing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaResearch Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, ChinaKey Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, ChinaJiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, ChinaLiver 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.https://www.frontiersin.org/article/10.3389/fcell.2020.00513/fullmicroRNA-98hepatic stellate cellliver fibrosisHLFHIF-1α |
| spellingShingle | 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 MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression Frontiers in Cell and Developmental Biology microRNA-98 hepatic stellate cell liver fibrosis HLF HIF-1α |
| title | MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression |
| title_full | MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression |
| title_fullStr | MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression |
| title_full_unstemmed | MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression |
| title_short | MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression |
| title_sort | microrna 98 inhibits hepatic stellate cell activation and attenuates liver fibrosis by regulating hlf expression |
| topic | microRNA-98 hepatic stellate cell liver fibrosis HLF HIF-1α |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.00513/full |
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