title: Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition.
abstract: Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center.
authors.forename: Tung-Hung
authors.initials: TH
authors.lastname: Su
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan;
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Graduate Institute of Clinical Medicine.
authors.forename: Ping
authors.initials: P
authors.lastname: Jao
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: National Center of Excellence for Clinical Trial and Research, Medical Research, and.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: Departments of Pathology and.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei 23142, Taiwan;
authors.forename: Tai-Chung
authors.initials: TC
authors.lastname: Tseng
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 10002, Taiwan;
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine.
authors.forename: Huei-Ru
authors.initials: HR
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: National Center of Excellence for Clinical Trial and Research, Medical Research, and chends@ntu.edu.tw kaojh@ntu.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, Medical Research, and chends@ntu.edu.tw kaojh@ntu.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Clinical Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, Genomics Research Center, Academia Sinica, Nankang, Taipei 11529, Taiwan chends@ntu.edu.tw kaojh@ntu.edu.tw kfchen1970@ntu.edu.tw.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D055166:Hepatic Stellate Cells / Q000187:drug effects; D006801:Humans; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009536:Niacinamide; D000077157:Sorafenib
keywords: SHP-1; STAT3; hepatic stellate cell; hepatitis B; liver fibrosis