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

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 (BMI1^high TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1^high TICs, which possess strong tumorigenicity and increased trans-intrahepatic biliary epithelial migration ability by secreting lysosomal cathepsin B (CTSB). Orthotopic liver implantation of BMI1^high 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.

SUBMITTER: Xu LB

PROVIDER: S-EPMC10624910 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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

Xu Lei-Bo LB Qin Yu-Fei YF Su Liangping L Huang Cheng C Xu Qiuping Q Zhang Rui R Shi Xiang-De XD Sun Ruipu R Chen Jiali J Song Zhixiao Z Jiang Xue X Shang Lihuan L Xiao Gang G Kong Xiangzhan X Liu Chao C Wong Ping-Pui PP

Nature communications 20231103 1

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 (BMI1<sup>high</sup> TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1<sup>high</sup> TI ...[more]

PMID: 37923799

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Project description:BackgroundHepatocellular carcinoma (HCC) associated with bile duct tumor thrombus (BDTT) is uncommon in clinical practice. Surgical resection can achieve better survival than non-operative palliative treatments. However, there is great controversy regarding the optimal surgical modality, particularly regarding the approach to remove BDTT in patients with HCC with macroscopic BDTT.MethodsData from consecutive patients who underwent radical surgery for HCC and macroscopic BDTT at the Eastern Hepatobiliary Surgery Hospital and Fujian Provincial Hospital from January 2009 to December 2016 were retrospectively reviewed. The survival outcomes of patients who underwent hepatectomy combined with extrahepatic bile duct resection (the EBDR group) were compared with those of patients undergoing liver resection plus thrombectomy (the thrombectomy group) using propensity score matching (PSM). Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS).Results217 patients included in this study were divided into two groups: the EBDR group (n=30) and the thrombectomy group (n=187). A total of 90 patients were matched by PSM with a 1:2 ratio. Before PSM, the OS and RFS rates were comparable between the two groups (for OS, P=0.517; for RFS, P=0.211). After PSM, the OS rates did not differ statistically significantly between the EBDR and thrombectomy groups (P=0.134). Nevertheless, the RFS rate of the EBDR group was significantly higher compared to that of the thrombectomy group (P=0.020). Multivariate analysis demonstrated that some traditional risk factors, such as tumor size and microscopic resection margin, were more important prognostic factors than the BDTT type.ConclusionsFor patients with HCC and macroscopic BDTT, hepatectomy combined with extrahepatic bile duct resection is associated with a reduced recurrence rate in comparison with concurrent thrombectomy. Further large-scale, prospective studies are warranted to evaluate the impact of different surgical modalities on these patients' survival.

Dataset Information

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

Publications

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

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