https://scholars.lib.ntu.edu.tw/handle/123456789/473313
標題: | Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition | 作者: | TUNG-HUNG SU Shiau C.-W Jao P CHEN-HUA LIU CHUN-JEN LIU Tai W.-T YUNG-MING JENG HUNG-CHIH YANG TAI-CHUNG TSENG HSIANG-PO HUANG Cheng H.-R PEI-JER CHEN Chen K.-F JIA-HORNG KAO DING-SHINN CHEN |
公開日期: | 2015 | 出版社: | National Academy of Sciences | 卷: | 112 | 期: | 23 | 起(迄)頁: | 7243-7248 | 來源出版物: | Proceedings of the National Academy of Sciences of the United States of America | 摘要: | 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. ? 2015 PNAS. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983718348&doi=10.1073%2fpnas.1507499112&partnerID=40&md5=7e9fa2863eb624e1ca20e528ea47f0de https://scholars.lib.ntu.edu.tw/handle/123456789/473313 |
ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1507499112 | SDG/關鍵字: | 3 (6 bromo 2 pyridinyl) 2 cyano n (1 phenylethyl)acrylamide; alpha smooth muscle actin; collagen; cyclin D1; interleukin 6; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein mcl 1; protein tyrosine phosphatase; protein tyrosine phosphatase SHP 1; Raf protein; sc 1; sorafenib; src homology protein tyrosine phosphatase 1; STAT3 protein; thioacetamide; unclassified drug; vanadate sodium; carbanilamide derivative; nicotinamide; sorafenib; STAT3 protein; STAT3 protein, human; animal cell; animal experiment; animal model; apoptosis; Article; bile duct ligation; cell death; cell proliferation; cell viability; chronic hepatitis B; clinical article; colony formation; comparative study; controlled study; disease severity; down regulation; enzyme activity; experimental liver fibrosis; flow cytometry; histopathology; human; human cell; human tissue; in vitro study; in vivo study; liver biopsy; liver fibrosis; male; mouse; nonhuman; priority journal; protein expression; rat; stellate cell; upregulation; Western blotting; analogs and derivatives; animal; antagonists and inhibitors; Bagg albino mouse; cell line; chemistry; drug effects; liver cirrhosis; Mus; Rattus; Animals; Cell Line; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Mice; Mice, Inbred BALB C; Niacinamide; Phenylurea Compounds; Rats; STAT3 Transcription Factor |
顯示於: | 病理學科所 |
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