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Cellular and Molecular Biology

Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis

British Journal of Cancer volume 128, pages 992–1004 (2023)Cite this article

Subjects

Abstract

Background

GRP78 has been implicated in hepatocarcinogenesis. However, the clinical relevance, biological functions and related regulatory mechanisms of GRP78 in hepatitis B virus (HBV)-associated hepatoma carcinoma (HCC) remain elusive.

Methods

The association between GRP78 expression and HBV-related HCC was investigated. The effects of HBV X protein (HBX) on GRP78 and MAN1B1 expression, biological functions of GRP78 and MAN1B1 in HBX-mediated HCC cells and mechanisms related to TRIM25 on GRP78 upregulation to induce MAN1B1 expression in HBX-related HCC cells were examined.

Results

GRP78 expression was correlated with poor prognosis in HBV-positive HCC. HBX increased MAN1B1 protein expression depending on GRP78, and HBX enhanced the levels of MAN1B1 to promote proliferation, migration and PI3-K/mTOR signalling pathway activation in HCC cells. GRP78 activates Smad4 via its interaction with Smad4 to increase MAN1B1 expression in HBX-expressing HCC cells. TRIM25 enhanced the stability of GRP78 by inhibiting its ubiquitination. HBX binds to GRP78 and TRIM25 and accelerates their interaction of GRP78 and TRIM25, leading to an increase in GRP78 expression.

Conclusions

HBX enhances the stability of GRP78 through TRIM25 to increase the expression of MAN1B1 to facilitate tumorigenesis, and we provide new insights into the molecular mechanisms underlying HBV-induced malignancy.

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Fig. 1: Clinical importance of GRP78 in HBV-related HCC and HBX contribute to GRP78 expression.
Fig. 2: Influence of GRP78 on the expression of MAN1B1 induced by HBX in HCC cells.
Fig. 3: GRP78 interacts with and activates Smad4 to facilitate MAN1B1 expression in hepatoma cells.
Fig. 4: Role of smad4 in the expression of GRP78 in HBX-expressing hepatoma cells.
Fig. 5: Role of TRIM25 in GRP78 stability in liver cancer cells.
Fig. 6: Effect of TRIM25 on the stability of GRP78 in HBX-positive HCC cells.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

The pattern graph used in Fig. 6n was created by BioRender (https://biorender.com/). The English language was edited by Editage (www.editage.cn). We thank Professor Wenshi Wang at Xuzhou Medical University for providing Huh7-NTCP and HepAD38 cells.

Funding

The study was supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Natural Science Foundation of the Jiangsu Higher Education Institutions (21KJA310004), Xuzhou Technology Bureau Foundation (KC21065), the Natural Science Foundation of Jiangsu Province (BK20211347) and Suqain Sci&Tech Program (K202015).

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Author notes

  1. These authors contributed equally: Hongjuan You, Ning Zhang, Tong Yu.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Hongjuan You, Ning Zhang, Tong Yu, Lihong Ma, Qi Li, Xing Wang, Dongchen Yuan, Delong Kong, Xiangye Liu, Fanyun Kong, Kuiyang Zheng & Renxian Tang

  2. Laboratory Department, The People’s Hospital of Funing, Yancheng, Jiangsu, China

    Qi Li

  3. Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu, China

    Wei Hu & Dongsheng Liu

  4. National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Kuiyang Zheng & Renxian Tang

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Contributions

HY, NZ and TY performed the experiments, analysed the experimental data and contributed equally to the present study. HY and FK wrote the manuscript. QL, DY, XW, LM, DK and XL performed laboratory work. WH and DL contribute to data analysis. KZ, FK and RT designed the work and checked the revised manuscript.

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Correspondence to Fanyun Kong or Renxian Tang.

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The present study was approved by the ethics committee of Xuzhou Medical University and the Animal Care and Use Committee at Xuzhou Medical University.

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You, H., Zhang, N., Yu, T. et al. Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis. Br J Cancer 128, 992–1004 (2023). https://doi.org/10.1038/s41416-022-02115-8

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