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BMI1 promotes cholangiocarcinoma progression and correlates with antitumor immunity in an exosome-dependent manner

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Abstract

Background

Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated.

Methods

In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells.

Conclusions

BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CCA:

Cholangiocarcinoma

iCCA:

Intrahepatic cholangiocarcinoma

pCCA:

Perihilar cholangiocarcinoma

dCCA:

Distal cholangiocarcinoma

TMA:

Tissue microarray

IHC:

Immunohistochemistry

qRT-PCR:

Quantitative real-time polymerase chain reaction

WB:

Western blot

IHC:

Immunohistochemistry

ELISA:

Enzyme-linked immunosorbent assays

ChIP-qPCR:

Chromatin immunoprecipitation-qPCR

OS:

Overall survival rate

DMEM:

Dulbecco's Modified Eagle Medium

FBS:

Fetal bovine serum

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

PVDF:

Polyvinylidene difluoride

PMSF:

Phenylmethanesulfonyl fluoride

PBS:

Phosphate buffer saline

CCK-8:

Cell counting kit-8

DMSO:

Dimethyl sulfoxide

CM:

Conditioned medium

BMI1:

B-cell-specific Moloney leukemia virus insertion site 1

E-cad:

E-cadherin

N-cad:

N-cadherin

EMT:

Epithelial-mesenchymal transition

MVBs:

Multivesicular bodies

shRNA:

Short hairpin RNA

TNM:

Tumor–node–metastasis

rhBMI1:

Recombinant human BMI1

exoBMI1:

Exosomal BMI1

CD8A:

CD8 antigen

CCL5:

C–C motif chemokine ligand 5

CXCL9:

C-X-C motif chemokine ligand 9

PD1:

Programmed cell death protein 1

ICB:

Immune checkpoint blocking

ICI:

Immune checkpoint inhibitors

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Acknowledgements

We thank Dr. Xiaoqing Yang from the Department of Pathology, the Qianfoshan Hospital of Shandong University, for evaluating the IHC results and distinguish different cell types in the HE staining.

Funding

This work was supported by the National Natural Science Foundation of China (Grant nos. 81900728, 82072676, 82172791), Shandong Province Natural Science Foundation (Grant nos. ZR2019MH008, ZR2020MH238), Shandong Province Key R&D Program (Major Scientific Innovation Projects, 2021CXGC011105), Shandong Medical and Health Technology Development Project (Grant no. 2018WSB20002), Clinical Research Foundation of Shandong University (Grant no. 2020SDUCRCA018), Key Research and Development Program of Shandong Province (Grant no. 2019GSF108254). The funders had no role in study design, data collection, analysis, interpretation, and manuscript writing.

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Author notes

  1. Zengli Liu, Chunxiao Hu, and Lijie Zheng have contributed equally.

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China

    Zengli Liu, Chunxiao Hu, Lijie Zheng, Jialiang Liu, Kangshuai Li, Xingyong Li, Yue Wang, Wentao Mu, Tianli Chen, Anda Shi, Bo Qiu, Zongli Zhang & Yunfei Xu

  2. Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 11 Wuyingshan Middle Road, Jinan, 250031, Shandong, China

    Xingyong Li

  3. Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China

    Xin Zhang

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  1. Zengli Liu
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  2. Chunxiao Hu
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  4. Jialiang Liu
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Contributions

ZL, CH, LJ, YW, and JL performed the experiments. ZL designed the experiments and wrote the paper. ZL, LZ, KL, and BQ collected the clinical samples. XL, YW, WM, TC, and AS perform the follow-up. ZL, CH, and LZ participated in data analysis and interpretation. XZ and YX designed the study, YX and ZZ contributed to study supervision and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zongli Zhang or Yunfei Xu.

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There are no relevant conflicts of interest.

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The study was approved by the Ethics Committee of Qilu Hospital of Shandong University, and written informed consent was obtained from each patient. The Laboratory Animal Care and Use Committees of the hospital approved all experimental procedures.

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Liu, Z., Hu, C., Zheng, L. et al. BMI1 promotes cholangiocarcinoma progression and correlates with antitumor immunity in an exosome-dependent manner. Cell. Mol. Life Sci. 79, 469 (2022). https://doi.org/10.1007/s00018-022-04500-1

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