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Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation

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  • Lei-Bo Xu

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Yu-Fei Qin

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Liangping Su

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Cheng Huang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Qiuping Xu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Rui Zhang

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xiang-De Shi

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Ruipu Sun

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Jiali Chen

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Zhixiao Song

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xue Jiang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Lihuan Shang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Gang Xiao

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xiangzhan Kong

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Chao Liu

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Ping-Pui Wong

    (Sun Yat-sen University
    Sun Yat-sen University)

Abstract

Bile duct tumor thrombosis (BDTT) is a complication mostly observed in patients with advanced hepatocellular carcinoma (HCC), causing jaundice and associated with poor clinical outcome. However, its underlying molecular mechanism is unclear. Here, we develop spontaneous preclinical HCC animal models with BDTT to identify the role of BMI1 expressing tumor initiating cells (BMI1high TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1high TICs, which possess strong tumorigenicity and increased trans-intrahepatic biliary epithelial migration ability by secreting lysosomal cathepsin B (CTSB). Orthotopic liver implantation of BMI1high TICs into mice generates tumors and triggers CTSB mediated bile duct invasion to form tumor thrombus, while CTSB inhibitor treatment prohibits BDTT and extends mouse survival. Clinically, the elevated serum CTSB level determines BDTT incidence in HCC patients. Mechanistically, BMI1 epigenetically up-regulates CTSB secretion in TICs by repressing miR-218-1-3p expression. These findings identify a potential diagnostic and therapeutic target for HCC patients with BDTT.

Suggested Citation

  • Lei-Bo Xu & Yu-Fei Qin & Liangping Su & Cheng Huang & Qiuping Xu & Rui Zhang & Xiang-De Shi & Ruipu Sun & Jiali Chen & Zhixiao Song & Xue Jiang & Lihuan Shang & Gang Xiao & Xiangzhan Kong & Chao Liu &, 2023. "Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42930-y
    DOI: 10.1038/s41467-023-42930-y
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    References listed on IDEAS

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    1. Wen Cai Zhang & Tan Min Chin & Henry Yang & Min En Nga & Declan Patrick Lunny & Edwin Kok Hao Lim & Li Li Sun & Yin Huei Pang & Yi Ning Leow & Shanneen Rossellini Y Malusay & Priscilla Xin Hui Lim & J, 2016. "Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    2. Ya-Ming Meng & Xue Jiang & Xinbao Zhao & Qiong Meng & Sangqing Wu & Yitian Chen & Xiangzhan Kong & Xiaoyi Qiu & Liangping Su & Cheng Huang & Minghui Wang & Chao Liu & Ping-Pui Wong, 2021. "Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
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