HBV PreS/S区基因突变诱导肝细胞内质网应激致肝细胞肝癌相关机制研究进展

doi:10.3969/j.issn.1673-8640.2024.12.017

摘要/Abstract

摘要：

乙型肝炎病毒（HBV）感染是一个全球性的公共卫生问题，可导致肝硬化和肝细胞肝癌（HCC）等多种疾病。HBV S区基因组编码大表面蛋白（LHB）、中表面蛋白（MHB）、小表面蛋白（SHB），其基因组突变形成的变异S蛋白会在肝细胞内质网中大量积累，进而产生内质网应激（ERS）现象。同时，ERS和内质网未折叠蛋白质反应（UPR）激活参与了HCC的发生、发展和对治疗的应答，在促HCC的发病机制中发挥重要作用。文章就HBV S区基因组突变引起变异S蛋白在内质网中堆积造成的ERS现象致HCC的相关研究进展进行综述。

关键词: 乙型肝炎病毒, S区基因突变, 内质网应激, 肝细胞肝癌

Abstract:

Hepatitis B virus（HBV） infection is a public global health problem that leads to a variety of diseases including cirrhosis and hepatocellular carcinoma（HCC）. HBV S region genome encodes hepatitis B virus large surface protein（LHB），hepatitis B virus middle surface protein（MHB） and hepatitis B virus small surface protein（SHB），and mutations in its genome that form variant S proteins accumulate in large quantities in the endoplasmic reticulum of hepatocytes，which in turn produce endoplasmic reticulum stress（ERS）. ERS and unfolded protein response（UPR） activation are involved in the onset，development and response to therapy of HCC and play roles in the pathogenesis of HCC. This review focuses on the progress of research related to ERS causing HCC by the accumulation of variant S proteins in the endoplasmic reticulum due to HBV PrsS/S region gene mutation.

Key words: Hepatitis B virus, S region gene mutation, Endoplasmic reticulum stress, Hepatocellular carcinoma

中图分类号:

R373.2

刘洋, 何成山, 蒋秀娣, 陆志成. HBV PreS/S区基因突变诱导肝细胞内质网应激致肝细胞肝癌相关机制研究进展[J]. 检验医学, 2024, 39(12): 1229-1233.

LIU Yang, HE Chengshan, JIANG Xiudi, LU Zhicheng. HBV PreS/S region gene mutation inducing hepatocyte endoplasmic reticulum stress causing hepatocellular carcinoma[J]. Laboratory Medicine, 2024, 39(12): 1229-1233.

图/表 1

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危险因素	UPR激活途径	肝损伤的细胞分子机制	参考文献
PreS区基因突变
PreS1缺失（核苷酸3040-3111）	GRP78和GRP94表达明显增强，激活PERK、JNK通路	PreS区基因缺失突变将导致MHB、SHB合成减少，LHB滞留在细胞中，形成GGH；有助于增加与HCC相关的环氧合酶、细胞周期蛋白A、核因子κB和ROS等因子的基因表达，诱导氧化应激和DNA损伤	[17]
PreS2缺失（核苷酸4-57） PreS2缺失（核苷酸15-56）	上调PERK、XBP1、ERO1L		[17]
G2950A/G2951A/A2962G/ C2964A	上调XBP1、ERO1L	PERK/CHOP轴、ERO1L和XBP1可促进细胞对缺氧微环境的耐受性，并改变线粒体的代谢功能；PreS突变激活的ERS也可能促进促癌性炎症；ERO1L和XBP1可激活白细胞介素-6通路并促进肝细胞癌发展	[25-26]
C3116T/T31C	上调PERK、XBP1、ERO1L		[25-26]
S区基因突变
W36L、T47K、N52D、 V184A、F220L	上调IRE-1α、ATF6、PERK、eIF2α、XBP1s、CHOP和GRP78	诱导ERS、ROS产生，促进细胞凋亡	[27]
W74L和L77R	突变型HBsAg保留在内质网和高尔基体中，GRP78基因和蛋白不上调	HBsAg在内质网和高尔基体中累积，导致肝细胞对γ干扰素或肿瘤坏死因子α产生超敏反应	[20]

危险因素	UPR激活途径	肝损伤的细胞分子机制	参考文献
PreS区基因突变
PreS1缺失（核苷酸3040-3111）	GRP78和GRP94表达明显增强，激活PERK、JNK通路	PreS区基因缺失突变将导致MHB、SHB合成减少，LHB滞留在细胞中，形成GGH；有助于增加与HCC相关的环氧合酶、细胞周期蛋白A、核因子κB和ROS等因子的基因表达，诱导氧化应激和DNA损伤	[17]
PreS2缺失（核苷酸4-57） PreS2缺失（核苷酸15-56）	上调PERK、XBP1、ERO1L		[17]
G2950A/G2951A/A2962G/ C2964A	上调XBP1、ERO1L	PERK/CHOP轴、ERO1L和XBP1可促进细胞对缺氧微环境的耐受性，并改变线粒体的代谢功能；PreS突变激活的ERS也可能促进促癌性炎症；ERO1L和XBP1可激活白细胞介素-6通路并促进肝细胞癌发展	[25-26]
C3116T/T31C	上调PERK、XBP1、ERO1L		[25-26]
S区基因突变
W36L、T47K、N52D、 V184A、F220L	上调IRE-1α、ATF6、PERK、eIF2α、XBP1s、CHOP和GRP78	诱导ERS、ROS产生，促进细胞凋亡	[27]
W74L和L77R	突变型HBsAg保留在内质网和高尔基体中，GRP78基因和蛋白不上调	HBsAg在内质网和高尔基体中累积，导致肝细胞对γ干扰素或肿瘤坏死因子α产生超敏反应	[20]