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Bmi1 drives hepatocarcinogenesis by repressing the TGFβ2/SMAD signalling axis

Oncogene volume 39, pages 1063–1079 (2020)Cite this article

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Abstract

Bmi1 is overexpressed in one-third of hepatocellular carcinoma (HCC) patients and acts as an oncogene in hepatocarcinogenesis. However, the underlying mechanism is unclear. The role of TGFβ signalling in HCC is not well defined as well. Here, we report that TGFβ2 is a target of Bmi1 in HCC and has a tumour-suppressing role. In Bmi1-knockout mouse livers and HCC cell lines, TGFβ2/SMAD cascade proteins were upregulated. TGFβ2 expression was inversely correlated with Bmi1 expression in human and mouse HCC tissues. In vitro, Bmi1 knockdown activated TGFβ2/SMAD signalling and led to cell apoptosis via upregulation of p15 and p21. TGFβ2 inhibition rescued the inhibitory effect of Bmi1 knockdown on HCC cell survival, proliferation, and cell-cycle progression. In vivo, restoration of TGFβ2 expression blocked Bmi1/Ras-driven hepatocarcinogenesis in mice. Chromatin immunoprecipitation and luciferase reporter assays revealed that Bmi1 repressed TGFβ2 expression by binding to its promoter as a co-factor of polycomb repressor complex 1. Our findings elucidate the molecular mechanism underlying hepatic Bmi1-driven carcinogenesis and highlight the importance of TGFβ2 as a tumour suppressor in HCC development.

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Acknowledgements

This study was supported by the National Science Foundation of China (81572723 and 81872253) and the Innovation Foundation of Higher Education of China (2016JCTD109).

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  1. These authors contributed equally: Bin Li, Yuyuan Chen

Authors and Affiliations

  1. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Bin Li, Yuyuan Chen, Jun Guo, Wen Fu, Yong Liu, Lei Li & Chuanrui Xu

  2. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China

    Fei Wang

  3. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Min Li & Qichang Zheng

  4. Stem Cell Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Lingling Fan

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Li, B., Chen, Y., Wang, F. et al. Bmi1 drives hepatocarcinogenesis by repressing the TGFβ2/SMAD signalling axis. Oncogene 39, 1063–1079 (2020). https://doi.org/10.1038/s41388-019-1043-8

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