Exosome-Mediated Bmi1 Promotes Cholangiocarcinoma Growth and Metastasis Through the Differential Regulation of miR-320b and miR-27b-3p

Abstract

Background: Bmi1 is up-regulated in many human malignancies. However, the role of Bmi1 in the progression of cholangiocarcinoma (CCA) remains largely undetermined. In the present study, we investigated the biological function and potential mechanisms of Bmi1 in the progression of CCA. Methods: The expression of Bmi1 was detected in 2 cohorts of human CCA tissues using immunohistochemistry. Function of Bmi1 or exosomal Bmi1 was investigated using CCK8, colony formation, transwell, vascular tube formation assays and tumour xenograft models. RNA-seq and miRNA-seq were used for identification of downstream targets and upstream regulation miRNAs. Findings: Bmi1 was significantly up-regulated in CCA tissues, and associated with tumour size and lymph nodes metastasis, which is an independent prognostic marker for CCA. Overexpresson of Bmi1 promoted CCA cells proliferation, migration, and invasion. And, depletion of Bmi1 could inhibit growth and metastases of CCA cells in vitro and in vivo. QBC-939-derived exosomes transferred Bmi1 to RBE cells and human umbilical vein endothelial cells, thus promoting proliferation, metastasis, and angiogenesis of CCA. Bmi1 is involved in regulation of p53 pathway and EMT in CCA. Based on the next-generation sequencing, we identified and verified Bmi1 was downregulated by miR-320b while upregulated by miR-27b-3p in CCA. Interpretation: Bmi1, or exosomal Bmi1, playes a critical role in tumourgenosis and metastasis of CCA, and can be served as a potential predictive biomarker for CAA prognosis. Funding: National Natural Science Foundation of China (No. 81900728); Shandong Province Natural Science Foundation (ZR2020MH238); Shandong Medical and Health Technology Development Project (2018WSB20002). Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Ethics Committee of Qilu Hospital of Shandong University, and written informed consent was obtained from each patient.