Zhao Baoxin, Qiao Hongxiu, Gao Zhiyun, Zhao Yan, Wang Weijie, Cui Yan, Li Fangxu, Wang Yuping, Guo Zhanjun, Chuai Xia, Chiu Sandra
State Key Laboratory of Virology and Biosafety Wuhan Institute of Virology Center For Biosafety Mega Science Chinese Academy of Sciences Wuhan Hubei China.
Department of Pathogen Biology Hebei Medical University Shijiazhuang Hebei China.
MedComm (2020). 2025 Sep 3;6(9):e70365. doi: 10.1002/mco2.70365. eCollection 2025 Sep.
Hepatitis B virus (HBV) precore G1896A mutation is closely associated with poor prognosis of liver disease. We previously revealed that the G1896A mutation could enhance HBV replication and promote hepatocellular carcinoma (HCC) cell growth both in vitro and in vivo. However, the in-depth mechanisms by which this mutation promotes the malignancy of HCC still need to be explored. Here, we examined the activation of endoplasmic reticulum (ER) stress and glycolysis in HBV G1896A mutation-associated HCC. Bioinformatics, chromatin immunoprecipitation assay and dual-luciferase assay were performed to give insight into the underlying molecular interaction between ER stress and glycolysis. Here, we observed that HBV G1896A mutation also promoted HCC cell invasion and migration. Furthermore, HBV G1896A mutation induced ER stress, and specifically, PERK-ATF4 pathway was responsible for the HCC cell malignancy. Mechanistically, PERK-ATF4 signaling induced transcriptional activation of PFKFB3, a key gene in the process of glycolysis. Finally, in vitro rescue experiments and in vivo efficacy studies revealed that the ATF4-PFKFB3 axis is necessary for the HCC tumor growth and metastasis. These results highlight that the ER stress and glycolysis are involved in the HCC-promotion function of HBV G1896A mutation, providing new insights into HBV-related HCC.
乙肝病毒（HBV）前核心区G1896A突变与肝病预后不良密切相关。我们之前揭示了G1896A突变可增强HBV复制，并在体外和体内促进肝细胞癌（HCC）细胞生长。然而，该突变促进HCC恶性进展的深入机制仍有待探索。在此，我们研究了内质网（ER）应激和糖酵解在HBV G1896A突变相关HCC中的激活情况。进行了生物信息学、染色质免疫沉淀分析和双荧光素酶分析，以深入了解ER应激与糖酵解之间潜在的分子相互作用。在此，我们观察到HBV G1896A突变也促进了HCC细胞的侵袭和迁移。此外，HBV G1896A突变诱导了ER应激，具体而言，PERK-ATF4通路是HCC细胞恶性进展的原因。机制上，PERK-ATF4信号传导诱导了糖酵解过程中的关键基因PFKFB3的转录激活。最后，体外挽救实验和体内疗效研究表明，ATF4-PFKFB3轴对于HCC肿瘤生长和转移是必需的。这些结果突出表明，ER应激和糖酵解参与了HBV G1896A突变促进HCC的功能，为HBV相关HCC提供了新的见解。
