HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway

Baoxin Zhao; Hongxiu Qiao; Yan Zhao; Zhiyun Gao; Weijie Wang; Yan Cui; Jian Li; Zhanjun Guo; Xia Chuai; Sandra Chiu

doi:10.1016/j.virs.2023.06.004

October 2023

Baoxin Zhao, Hongxiu Qiao, Yan Zhao, Zhiyun Gao, Weijie Wang, Yan Cui, Jian Li, Zhanjun Guo, Xia Chuai and Sandra Chiu. HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway[J]. Virologica Sinica, 2023, 38(5): 680-689. doi: 10.1016/j.virs.2023.06.004

Citation: Baoxin Zhao, Hongxiu Qiao, Yan Zhao, Zhiyun Gao, Weijie Wang, Yan Cui, Jian Li, Zhanjun Guo, Xia Chuai, Sandra Chiu. HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway .VIROLOGICA SINICA, 2023, 38(5) : 680-689. http://dx.doi.org/10.1016/j.virs.2023.06.004

乙肝病毒preC基因G1896A突变通过激活ERK/MAPK信号通路促进肝癌细胞生长

赵宝鑫 ^a,b ,
乔红秀 ^a,b ,
赵艳 ^a,b ,
高志云 ^a,b ,
王卫杰 ^a,b ,
崔岩 ^a,b ,
李剑 ^b ,
郭占军 ^c,, ,
揣侠 ^b,d,, ,
Sandra Chiu ^a,e,,

a. 河北医科大学, 医学与健康研究院;
b. 河北医科大学, 病原生物学教研室;
c. 河北医科大学第四医院;
d. 中国科学院武汉病毒研究所;
e. 中国科学技术大学, 生命科学与医学部

通讯作者： 郭占军, zjguo5886@aliyun.com; 揣侠, chuaixia@wh.iov.cn; Sandra Chiu, qiux@ustc.edu.cn
收稿日期： 2023-03-29
录用日期： 2023-06-14

摘要

慢性乙肝病毒（HBV）感染是导致肝细胞癌（HCC）的主要原因。HBV基因组容易发生突变，多种突变与肝脏疾病的恶性程度密切相关。G1896A突变（HBV基因组1896位的G突变为A）是HBV preC基因最常见的突变之一，它可以抑制HBeAg的表达，并且与HCC进展密切相关。然而，这种突变影响HCC进展的机制尚不清楚。本研究发现，G1896A突变可以显著增强HBV体外复制，增强HCC细胞对索拉非尼的耐药性，并促进肝癌进展。从机制上讲，G1896A突变可以激活ERK/MAPK通路，促进HCC细胞增殖，抑制HCC细胞凋亡。总的来说，我们的研究首次证明了G1896A突变在加剧HCC严重程度方面具有双重调节作用，并为G1896A突变相关HCC患者的治疗提供了一些启示。
- 乙肝病毒
- , G1896A突变
- , 肝细胞癌
- , 增殖
- , 凋亡
- , ERK/MAPK

HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway

Baoxin Zhao ^a,b ,
Hongxiu Qiao ^a,b ,
Yan Zhao ^a,b ,
Zhiyun Gao ^a,b ,
Weijie Wang ^a,b ,
Yan Cui ^a,b ,
Jian Li ^b ,
Zhanjun Guo ^c,, ,
Xia Chuai ^b,d,, ,
Sandra Chiu ^a,e,,

a. Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China;
b. Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China;
c. Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China;
d. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, 430207, China;
e. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China

Corresponding author: Zhanjun Guo, zjguo5886@aliyun.com Xia Chuai, chuaixia@wh.iov.cn Sandra Chiu, qiux@ustc.edu.cn
Received Date: 29 March 2023
Accepted Date: 14 June 2023

Abstract

Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.
- HBV G1896A mutation
- , Hepatocellular carcinoma (HCC)
- , Proliferation
- , Apoptosis
- , ERK/MAPK

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