The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis

被引：63
作者：
Wang, Zhuo [1 ,2 ,3 ]
Li, Jia'an [2 ,3 ]
Xiao, Wen'ang [2 ,3 ]
Long, Jiafu [1 ,4 ]
Zhang, Hongmin [2 ,3 ]
机构：
[1] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China
[2] Southern Univ Sci & Technol, Dept Biol, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen Key Lab Cell Microenvironm, Shenzhen 518055, Peoples R China
[3] Southern Univ Sci & Technol, SUSTech HKU Joint Labs Matrix Biol & Dis, Shenzhen 518055, Peoples R China
[4] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China
来源：
LABORATORY INVESTIGATION | 2018年 / 98卷 / 12期
基金：
中国国家自然科学基金;
关键词：
HEPATIC STELLATE CELLS; ENDOTHELIAL GROWTH-FACTOR; TGF-BETA; SIGNAL TRANSDUCER; TRANSCRIPTION; PROMOTES FIBROSIS; ACTIVATOR; SORAFENIB; VEGF; INFLAMMATION;
D O I：
10.1038/s41374-018-0127-3
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 ( NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of alpha-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGF beta 1 and TGF beta RII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGF beta 1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.
引用
收藏
页码：1600 / 1613
页数：14
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