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.
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.
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.
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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The data that support the findings of this study are available from the corresponding authors upon reasonable request.
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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).
The authors declare no competing interests.
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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 (2023). https://doi.org/10.1038/s41416-022-02115-8