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Taraxasterol suppresses the growth of human liver cancer by upregulating Hint1 expression

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Abstract

Taraxasterol has potent anti-inflammatory and anti-tumor activity. However, the effect and potential mechanisms of Taraxasterol on the growth of human liver cancer have not been clarified. Histidine triad nucleotide-binding protein 1 (Hint1) is a tumor suppressor and its downregulated expression is associated with the development of cancer. Here, we report that Taraxasterol treatment significantly suppressed cell proliferation and induced cell cycle arrest at G0/G1 phase and apoptosis in liver cancer cells, but not in non-tumor hepatocytes. Furthermore, Taraxasterol upregulated Hint1 and Bax, but downregulated Bcl2 and cyclin D1 expression, accompanied by promoting the demethylation in the Hint1 promoter region in liver cancer cells. The effects of Taraxasterol were abrogated by Hint1 silencing and partially mitigated by Bax silencing, Bcl2 or cyclin D1 over-expression in HepG2 cells. Moreover, oral administration with Taraxasterol did not affect body weight, urinary protein levels, and the heart, liver, and kidney morphology in BALB/c mice but effectively inhibited the growth of implanted SK-Hep1 tumor in vivo. Collectively, we demonstrate that Taraxasterol inhibits the growth of liver cancer at least partially by enhancing Hint1 expression to regulate Bax, Bcl2, and cyclin D1 expression. Taraxasterol may be a drug candidate for the treatment of human liver cancer.

Key messages

  • Taraxasterol inhibits growth and induces apoptosis in human liver cancer cells.

  • Taraxasterol enhances Hint1 expression by promoting demethylation in Hint1 promoter.

  • Taraxasterol increases Hint1 levels to regulate Bax, Bcl2, and cyclinD1 expression.

  • The effects of Taraxasterol are abrogated by Hint1 silencing in liver cancer cells.

  • Taraxasterol inhibits the growth of subcutaneously implanted liver cancers in mice.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (grant numbers 81360360 and 81660399), the Innovative Research Team Project of Yunnan Institutions of Higher Education (no specific number), the Innovative Research Team Project of Yunnan Province (grant number 2015HC033), the Yunnan Provincial Academician Workstation of Xiaoping Chen (grant number 2017IC018), the Breeding Program for Major Scientific and Technological Achievements of Kunming Medical University (grant number CGYP201607), the Medical Leading Talent Project of Yunnan Province (grant number L201622), and the Yunnan Provincial Engineering Research Center of Major Surgical Diseases (no specific number) to L. Wang, the “Ten, Hundred, and Thousand Medical Talents of Kunming City” Project (grant number SW(tech)-33), the Medical Reserve Talent Project of Yunnan Province (grant number H201613), and the Yunnan Provincial Applied Fundamental Research (grant number 2017FE467 (-152)) to T.H. Bao, and the Scientific Research Foundation of Yunnan Province Office of Education (grant number 2016ZZX093) to W.W. Wang. We thank all individuals who have contributed to this study, especially Xu Meng (The First Hospital of Kunming, Kunming, China) and Li Chen (The Kunming Children’s Hospital, Kunming, China) for their participation in the preliminary experiments.

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Author notes

  1. Tianhao Bao, Yang Ke, Yifan Wang, and Weiwei Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Kunrui Road, Wuhua District, Kunming, 650101, Yunnan, China

    Tianhao Bao, Yang Ke, Yuehua Li & Lin Wang

  2. Mental Health Center of Kunming Medical University, Kunming, 650224, China

    Tianhao Bao

  3. School of Medicine, Yunnan University, 2 Cuihu North Road, Wuhua District, Kunming, 650091, Yunnan, China

    Tianhao Bao & Chunjie Xiao

  4. School of Stomatology, Shandong University, Jinan, 250012, China

    Yifan Wang

  5. Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China

    Weiwei Wang

  6. Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China

    Yan Wang & Xiang Kui

  7. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Qixin Zhou

  8. Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary

    Han Zhou

  9. Department of Hepatobiliary Surgery, The Sixth People’s Hospital of Chengdu, Chengdu, 610051, China

    Cheng Zhang

  10. Environment and Health Research Center, Southwest China Eco-development Academy, Southwest Forestry University, Kunming, 650224, China

    Dongming Zhou

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  1. Tianhao Bao
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  2. Yang Ke
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  9. Han Zhou
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Correspondence to Lin Wang or Chunjie Xiao.

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Bao, T., Ke, Y., Wang, Y. et al. Taraxasterol suppresses the growth of human liver cancer by upregulating Hint1 expression. J Mol Med 96, 661–672 (2018). https://doi.org/10.1007/s00109-018-1652-7

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  • DOI: https://doi.org/10.1007/s00109-018-1652-7

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