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

Laboratory Investigationvolume 98pages16001613 (2018) | Download Citation

Abstract

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 α-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 TGFβ1 and TGFβRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFβ1. 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.

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Acknowledgements

This work was partly supported by Guangdong Science and Technology Program (2017B030301018), research grants from Shenzhen Science and Technology Innovation Committee (JCYJ20160608140912962 and ZDSYS20140509142721429) and National Natural Science Foundation of China (31670753).

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Affiliations

  1. College of Life Sciences, Nankai University, Tianjin, 300071, China

    • Zhuo Wang
    •  & Jiafu Long
  2. Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU Joint Laboratories for Matrix Biology and Diseases, Southern University of Science and Technology, Shenzhen, 518055, China

    • Zhuo Wang
    • , Jia’an Li
    • , Wen’ang Xiao
    •  & Hongmin Zhang
  3. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China

    • Jiafu Long

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The authors declare no conflict of interest.

Corresponding authors

Correspondence to Zhuo Wang or Hongmin Zhang.

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https://doi.org/10.1038/s41374-018-0127-3