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Bufalin inhibits hepatitis B virus-associated hepatocellular carcinoma development through androgen receptor dephosphorylation and cell cycle-related kinase degradation

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Abstract

Purpose

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), which has a male predominance, lacks effective therapeutic options. Previously, the cardiac glycoside analogue bufalin has been found to inhibit HBV infection and HCC development. As yet, however, its molecular role in HBV-associated HCC has remained obscure.

Methods

Colony formation and soft agar assays, xenograft and orthotopic mouse models and HBV X protein (HBx) transgenic mice with exposure to diethylnitrosamine were used to evaluate the effect of bufalin on HBV-associated HCC growth and tumorigenicity. HBx-induced oncogenic signaling regulated by bufalin was assessed using PCR array, chromatin immunoprecipitation, site-directed mutagenesis, luciferase reporter, transcription and protein expression assays. Synergistic HCC therapeutic effects were examined using combinations of bufalin and sorafenib.

Results

We found that bufalin exerted a more profound effect on inhibiting the proliferation of HBV-associated HCC cells than of non HBV-associated HCC cells. Bufalin significantly inhibited HBx-induced malignant transfromation in vitro and tumorigenicity in vivo. Androgen receptor (AR) signaling was found to be a target of bufalin resistance to HBV-associated hepatocarcinogenesis. We also found that bufalin induced both AR dephosphorylation and cell cycle-related kinase (CCRK) degradation to inhibit β-catenin/TCF signaling, which subsequently led to cell cycle arrest via cyclin D1 down-regulation and p21 up-regulation, resulting in HCC regression. Furthermore, we found that bufalin reduced > 60% diethylnitrosamine-induced hepatocarcinogenesis in HBx transgenic mice, and improved the sensitivity of refractory HBV-associated HCC cells to sorafenib treatment.

Conclusion

Our results indicate that bufalin acts as a potential anti-HCC therapeutic candidate to block HBx-induced AR/CCRK/β-catenin signaling by targeting AR and CCRK, which may provide a novel strategy for the treatment of HBV-associated HCC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81774240, 81874436, 81673935, 81673938, 81672789, 81603589, 81774256 and 81673767), the Natural Science Foundation of Heilongjiang Province (H2017013), the Chenguang Program from Shanghai Education Development Foundation and Shanghai Municipal Education Commission (15CG48), the Shanghai Rising-star Program (17QA1403900), the Training plan of outstanding young medical talents, Shanghai Municipal Health Bureau (2017YQ021), the Talent Youth Supporting project sponsored by the Chinese Medicine Association (QNRC2-C14), the Training Plan for Excellent Academic Leaders of Shanghai Health System (2017BR007), the Science Research Project of Thirteen Five-year Plan (2018ZX10725504), the Shanghai science and Technology Commission support project (16401970600), Siming Scholar from Shanghai Shuguang Hospital (SGXZ-201904), and the Chinese medicine preponderant disease breeding project (zybz-2017004).

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Authors and Affiliations

  1. Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528. Zhangheng Road, Pudong New District, Shanghai, People’s Republic of China

    Zhuo Yu, Yunhui Zhuo, Xiaojun Zhu, Lingying Huang, Chao Zheng, Yun Jiang, Fan Le, Xuehua Sun & Yueqiu Gao

  2. Department of pharmacology, School of Pharmacy, Harbin Medical University, Harbin, People’s Republic of China

    Hai Feng

  3. Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China

    Man Li, Xin Zhang, Zhenhua Zhou & Yueqiu Gao

  4. Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Republic of Korea

    Dae-Yeul Yu

  5. School of Biomedical Sciences, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China

    Alfred Szelok Cheng

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  1. Zhuo Yu
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Contributions

Study concept and design: Z.Y., X.H.S., Y.Q.G.; acquisition of data: Z.Y., H.F., Y.H.Z., M.L., X.J.Z.; analysis and interpretation of data: L.Y.H., X.Z., Z.H.Z., C.Z.; drafting of the manuscript: Z.Y., H.F.; critical revision of the manuscript for important intellectual content: X.H.S., Y.Q.G.; statistical analysis: Y.J., F.L.; administrative, technical or material support: D.-Y.Y., A.S.L.C.; study supervision: Z.Y., X.H.S., Y.Q.G.

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Correspondence to Zhuo Yu, Xuehua Sun or Yueqiu Gao.

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Yu, Z., Feng, H., Zhuo, Y. et al. Bufalin inhibits hepatitis B virus-associated hepatocellular carcinoma development through androgen receptor dephosphorylation and cell cycle-related kinase degradation. Cell Oncol. 43, 1129–1145 (2020). https://doi.org/10.1007/s13402-020-00546-0

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