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

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 () and Ping-Pui Wong ()
Additional contact information
Lei-Bo Xu: Sun Yat-sen University
Yu-Fei Qin: Sun Yat-sen University
Liangping Su: Sun Yat-sen University
Cheng Huang: Sun Yat-sen University
Qiuping Xu: Sun Yat-sen University
Rui Zhang: Sun Yat-sen University
Xiang- De Shi: Sun Yat-sen University
Ruipu Sun: Sun Yat-sen University
Jiali Chen: Sun Yat-sen University
Zhixiao Song: Sun Yat-sen University
Xue Jiang: Sun Yat-sen University
Lihuan Shang: Sun Yat-sen University
Gang Xiao: Sun Yat-sen University
Xiangzhan Kong: Sun Yat-sen University
Chao Liu: Sun Yat-sen University
Ping-Pui Wong: Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42930-y

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