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Cellular and Molecular Biology

Bmi1 represses HLF to drive the formation and development of intrahepatic cholangiocarcinoma

British Journal of Cancer volume 134, pages 33–44 (2026)Cite this article

Subjects

Abstract

Background

Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent type of primary liver cancer and lacks effective targeted therapy. Previously, we reported that B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1) drives the formation and development of ICC independent of Ink4A/Arf; however, the underlying mechanism remains unclear. Here, we report that hepatic leukaemia factor (HLF) acts as a tumour-suppressor gene in ICC and Bmi1 represses HLF to drive ICC initiation and progression.

Methods

RNA sequencing was performed to find the downstream target of Bmi1 in ICC. Bioinformatic analysis and molecular biological techniques were used to examine the expression of Bmi1 and HLF in ICC. Effects of HLF silence or overexpression by lentivirus on cell proliferation or development were evaluated in human ICC cells, xenograft and primary ICC mouse models, respectively. The luciferase reporter assay was used to identify that Bmi1 regulates HLF.

Results

In ICC, HLF expression levels were inversely correlated with Bmi1. Overexpression of HLF inhibited the growth of ICC both in vitro and in vivo, whereas HLF knockout promoted ICC development in ICC mouse models. Importantly, HLF repression reversed the inhibitory effects of Bmi1 knockdown on cell survival, proliferation and colony formation. Luciferase reporter assay results indicated that Bmi1 represses HLF by directly binding to its promoter.

Conclusions

These findings revealed the molecular mechanism through which Bmi1 promotes ICC formation and development and uncovered the role of HLF as a tumour suppressor in ICC.

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Fig. 1: Screening of Bmi1 target genes in Bmi1/NRas mouse ICC tissues and human REB and QBC-939 ICC cell lines using RNA sequencing.
Fig. 2: HLF expression is low in ICC and negatively correlates with Bmi1.
Fig. 3: HLF overexpression inhibits ICC cell growth in vitro.
Fig. 4: HLF overexpression inhibits the growth of ICC allografts in nude mice.
Fig. 5: HLF overexpression delays ICC tumour formation induced by Bmi1 and NRas in mice.
Fig. 6: HLF knockout promotes the development of ICC.
Fig. 7: Knockdown of HLF restores the ICC cell growth inhibited by Bmi1 KD.
Fig. 8: Bmi1 inhibits HLF transcription in ICC by binding to its promoter.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or its Supplementary Materials]. The raw data of the RNA sequence were uploaded to the NCBI SRA Submission platform (Accession number: PRJNA1202219), and the data will be released upon receipt of this article.

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Acknowledgements

The authors thank all the members of the Dr Xu laboratory for their technical assistance and helpful discussions.

Funding

This work was supported by the National Science Foundation of China (82372667, 82273059 and 82073091) and Guizhou Province Science and Technology Project (ZK-2024-Key-097).

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Author notes

  1. These authors contributed equally: Jun Guo, Xiabing Shi.

Authors and Affiliations

  1. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jun Guo

  2. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiabing Shi, Yan Sun, Ruitao Long & Chuanrui Xu

  3. Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiabing Shi & Hua Wu

  4. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Feng Ye

  5. Department of Pharmacy, Tongren Polytechnic College, Tongren, P. R. China

    Chuanrui Xu

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Contributions

CX contributed to the conception and the design of the study. JG, XS and RL performed the experiments and contributed to the acquisition of data. HW contributed to the analysis and interpretation of data. FY contributed to manuscript drafting or critical revisions on the intellectual content. CX finalised the manuscript. JG and CX confirm the authenticity of all the raw data. YS contributed to the revision of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Feng Ye or Chuanrui Xu.

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Guo, J., Shi, X., Sun, Y. et al. Bmi1 represses HLF to drive the formation and development of intrahepatic cholangiocarcinoma. Br J Cancer 134, 33–44 (2026). https://doi.org/10.1038/s41416-025-03234-8

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