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HBx promotes hepatocarcinogenesis by enhancing phosphorylation and blocking ubiquitinylation of UHRF2

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Abstract

Background and aims

The major cause of Hepatocellular carcinoma (HCC) is acute or chronic infection caused by hepatotropic viruses and HBV infection is the main cause. UHRF2, a ubiquitin-protein ligase E3, is associated with cancer development. This study aimed to investigate the connection and mechanism between UHRF2 and HBV-associated HCC.

Methods

The expression of UHRF2 in human HBV-positive HCC tissues and paracancerous tissues was detected by western blot and tissue microarray. The effects of UHRF2 on invasion, migration and proliferation were detected in HBV-positive hepatoma cell lines. Furthermore, western blot, immunofluorescence, Co-immunoprecipitation and ubiquitination assays were used to explore the relationship and mechanism between UHRF2 and HBV-associated HCC.

Results

HBV-positive HCC tissues had higher UHRF2 expression levels than adjacent non-tumor tissues. The HBV-positive HCC patients with a low UHRF2 level in cancer tissues had longer overall and recurrence-free survival compared with those with a high UHRF2 level. UHRF2 induced invasion, migration and proliferation in human HBV-positive HCC cell lines HepG2.2.15 and Hep AD38(−). HBx, an encoding protein of HBV, maintained the stability of UHRF2 by blocking the ubiquitination of UHRF2. HBx up-regulated CDK2 expression through ETS1. UHRF2 bound to CDK2 directly and enhanced UHRF2 phosphorylation at serine 643.

Conclusions

These results suggest that HBx-ETS1-CDK2-UHRF2 pathway plays an important role in the pathogenesis of HBV-associated HCC and represents new therapeutic targets for human HCC.

Clinical Trials Registration

ChiCTR2000041416.

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Acknowledgements

We thank Dr. Rui Yang and Yan Sun for their technical supports.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81772178) and Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University (2019).

Author information

Author notes

  1. Fengjuan Cheng and Guanhua Qian contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China

    Fengjuan Cheng, Xianyun Fang, Jingjie Sun, Siyuan Chen, Rongjuan Chen, Shangjing Liu, Zhaodi Li, Kejia Wu & Changzhu Duan

  2. Key Medical Laboratory of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China

    Guanhua Qian

  3. Department of Hepatobillary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China

    Shiming Jiang & Yong Chen

  4. Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China

    Ni Tang & Juan Chen

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  1. Fengjuan Cheng
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Contributions

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript. FC and GQ contributed equally to this work.

Corresponding author

Correspondence to Changzhu Duan.

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Conflict of interest

Fengjuan Cheng, Guanhua Qian, Xianyun Fang, Jingjie Sun, Siyuan Chen, Rongjuan Chen, Shangjing Liu, Zhaodi Li, Kejia Wu, Shiming Jiang, Yong Chen, Ni Tang, Juan Chen, and Changzhu Duan declare that they have no conflict of interest.

Ethics approval

This study was performed in accordance with the declaration of Helsinki. HBV-positive HCC tissue samples and paired adjacent normal tissues were collected from the First Affiliated Hospital of Chongqing Medical University. Usage of these patient tissue samples was approved by the Ethics Committee of Chongqing Medical University (committee’s reference number: 2018027).

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Cheng, F., Qian, G., Fang, X. et al. HBx promotes hepatocarcinogenesis by enhancing phosphorylation and blocking ubiquitinylation of UHRF2. Hepatol Int 15, 707–719 (2021). https://doi.org/10.1007/s12072-021-10172-z

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  • DOI: https://doi.org/10.1007/s12072-021-10172-z

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