Jiannan Qiu1,2, Shasha Wu3, Peng Wang1, Yan Zhou4, Zhongxia Wang5, Yong Sun6, Chunping Jiang7. 1. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, Jiangsu, People's Republic of China. 2. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, People's Republic of China. 3. Department of Clinical Medicine and Rehabilitation, Jiangsu College of Nursing, Huai'an, 223005, People's Republic of China. 4. Department of Hepatobiliary Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, 210000, Jiangsu, People's Republic of China. 5. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, Jiangsu, People's Republic of China. freud_t@126.com. 6. Department of Hepatobiliary Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223001, Jiangsu, People's Republic of China. hayysunyong@126.com. 7. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, Jiangsu, People's Republic of China. chunpingjiang@163.com.
Abstract
BACKGROUND AND AIMS: Numerous studies have demonstrated that hepatic fibrosis, a progressive condition as an endpoint of multiple chronic hepatic diseases, is largely characterized with the extensive activation of hepatic stellate cells (HSCs). The precise effect of miR-488-5p in HSCs during hepatic fibrosis has not been elucidated. METHODS: In our study, qRT-PCR was applied to assess the level of miR-488-5p in activated HSCs stimulated by TGF-β1. We built murine liver fibrosis models with carbon tetrachloride (CCl4), high-fat diet (HFD) and bile duct ligation (BDL). In vitro, the effects of miR-488-5p in HSCs were examined through cell proliferation assay and apoptosis. Luciferase reporter assay was applied to identify the underlying target of miR-488-5p. In vivo, the effects of miR-488-5p were explored through mouse liver fibrosis models. RESULTS: The reduction of miR-488-5p in the activated HSCs induced by TGF-β1 and three mouse hepatic fibrosis models were identified. The in vitro functional experimentations verified that miR-488-5p restrained expression of fibrosis-related markers and proliferative capacity in HSCs. Mechanically, we identified that miR-488-5p inhibited tet methylcytosine dioxygenase 3 (TET3) expression via straightly binding onto the 3' UTR of its mRNA, which sequentially restrained the TGF-β/Smad2/3 pathway. TET3 inhibition induced by the overexpression of miR-488-5p reduced extracellular matrix deposition, which contributed to mitigating mouse liver fibrosis. CONCLUSION: We highlight that miR-488-5p restrains the activation of HSCs and hepatic fibrosis via targeting TET3 which is involved in the TGF-β/Smad2/3 signaling pathway. Collectively, miR-488-5p is identified as a potential therapeutic target for hepatic fibrosis.
BACKGROUND AND AIMS: Numerous studies have demonstrated that hepatic fibrosis, a progressive condition as an endpoint of multiple chronic hepatic diseases, is largely characterized with the extensive activation of hepatic stellate cells (HSCs). The precise effect of miR-488-5p in HSCs during hepatic fibrosis has not been elucidated. METHODS: In our study, qRT-PCR was applied to assess the level of miR-488-5p in activated HSCs stimulated by TGF-β1. We built murine liver fibrosis models with carbon tetrachloride (CCl4), high-fat diet (HFD) and bile duct ligation (BDL). In vitro, the effects of miR-488-5p in HSCs were examined through cell proliferation assay and apoptosis. Luciferase reporter assay was applied to identify the underlying target of miR-488-5p. In vivo, the effects of miR-488-5p were explored through mouse liver fibrosis models. RESULTS: The reduction of miR-488-5p in the activated HSCs induced by TGF-β1 and three mouse hepatic fibrosis models were identified. The in vitro functional experimentations verified that miR-488-5p restrained expression of fibrosis-related markers and proliferative capacity in HSCs. Mechanically, we identified that miR-488-5p inhibited tet methylcytosine dioxygenase 3 (TET3) expression via straightly binding onto the 3' UTR of its mRNA, which sequentially restrained the TGF-β/Smad2/3 pathway. TET3 inhibition induced by the overexpression of miR-488-5p reduced extracellular matrix deposition, which contributed to mitigating mouse liver fibrosis. CONCLUSION: We highlight that miR-488-5p restrains the activation of HSCs and hepatic fibrosis via targeting TET3 which is involved in the TGF-β/Smad2/3 signaling pathway. Collectively, miR-488-5p is identified as a potential therapeutic target for hepatic fibrosis.