HBV PreS/S region gene mutation inducing hepatocyte endoplasmic reticulum stress causing hepatocellular carcinoma

doi:10.3969/j.issn.1673-8640.2024.12.017

Abstract

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

CLC Number:

R373.2

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.

Figures/Tables 1

References 37

[1]	WEI J, FANG D. Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma[J]. Int J Mol Sci, 2021, 22(4):1799.
[2]	中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华传染病杂志, 2023, 41(1):3-28.
[3]	HUI Z, YU W, FUZHEN W, et al. New progress in HBV control and the cascade of health care for people living with HBV in China:evidence from the fourth national serological survey,2020[J]. Lancet Reg Health West Pac, 2024,51:101193.
[4]	CHEN X, CUBILLOS-RUIZ J R. Endoplasmic reticulum stress signals in the tumour and its microenvironment[J]. Nat Rev Cancer, 2021, 21(2):71-88. DOI PMID
[5]	LUO H, JIAO Q, SHEN C, et al. Unraveling the roles of endoplasmic reticulum-associated degradation in metabolic disorders[J]. Front Endocrinol(Lausanne), 2023,14:1123769.
[6]	JACKSON K G, WAY G W, ZENG J, et al. The dynamic role of endoplasmic reticulum stress in chronic liver disease[J]. Am J Pathol, 2023, 193(10):1389-1399. DOI PMID
[7]	毛瑞涛, 陈伟, 李自慧, 等. 重组pEGFP-C1-CXCL1真核表达载体构建及其对内质网应激下人肝癌细胞HepG2的增殖作用[J]. 军事医学, 2017, 41(10):792-795.
[8]	HU T, WANG J, LI W, et al. Endoplasmic reticulum stress in hepatitis B virus and hepatitis C virus infection[J]. Viruses, 2022, 14(12):2630.
[9]	BARTOSZEWSKA S, SAWSKI J, COLLAWN J F, et al. Dual RNase activity of IRE1 as a target for anticancer therapies[J]. J Cell Commun Signal, 2023, 17(4):1145-1161.
[10]	RUAN L, LI F, LI S, et al. Effect of different exercise intensities on hepatocyte apoptosis in HFD-induced NAFLD in rats:the possible role of endoplasmic reticulum stress through the regulation of the IRE1/JNK and eIF2α/CHOP signal pathways[J]. Oxid Med Cell Longev, 2021,2021:6378568.
[11]	XING Y, LIU Y, QI Z, et al. LAGE 3 promoted cell proliferation,migration,and invasion and inhibited cell apoptosis of hepatocellular carcinoma by facilitating the JNK and ERK signaling pathway[J]. Cell Mol Biol Lett, 2021, 26(1):49.
[12]	GUO Y, GUO R, SU Y, et al. The PERK/eIF2α/ATF4/CHOP pathway plays a role in regulating monocrotaline-induced endoplasmic reticulum stress in rat liver[J]. Res Vet Sci, 2020,130:237-239.
[13]	AJOOLABADY A, KAPLOWITZ N, LEBEAUPIN C, et al. Endoplasmic reticulum stress in liver diseases[J]. Hepatology, 2023, 77(2):619-639.
[14]	中华医学会肝病学分会肝癌学组. HBV/HCV相关肝细胞癌抗病毒治疗专家共识(2021年更新版)[J]. 中华肝脏病杂志, 2021, 29(10):948-966.
[15]	GERETS H H, TILMANT K, GERIN B, et al. Characterization of primary human hepatocytes,HepG2 cells,and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins[J]. Cell Biol Toxicol, 2012, 28(2):69-87.
[16]	LI Y, XIA Y, CHENG X, et al. Hepatitis B surface antigen activates unfolded protein response in forming ground glass hepatocytes of chronic hepatitis B[J]. Viruses, 2019, 11(4):386.
[17]	WANG H C, WU H C, CHEN C F, et al. Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress[J]. Am J Pathol, 2003, 163(6):2441-2449.
[18]	KIM H, LEE S A, WON Y S, et al. Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity[J]. World J Gastroenterol, 2015, 21(6):1794-1803.
[19]	CHOI Y M, LEE S Y, KIM B J. Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contribution to the progression of hepatocellular carcinoma[J]. Int J Mol Sci, 2019, 20(3):597.
[20]	KIM J Y, GARCIA-CARBONELL R, YAMACHIKA S, et al. ER stress drives lipogenesis and steatohepatitis via Caspase-2 activation of S1P[J]. Cell, 2018, 175(1):133-145. DOI PMID
[21]	JIANG D, ZHANG L, LIU W, et al. Trends in cancer mortality in China from 2004 to 2018:a nationwide longitudinal study[J]. Cancer Commun(Lond), 2021, 41(10):1024-1036.
[22]	曹广文. 我国原发性肝癌的流行病学特征及精准防控[J]. 广西医科大学学报, 2024, 41(11):1455-1463.
[23]	CHEN S, ZHANG Z, WANG Y, et al. Using quasispecies patterns of hepatitis B virus to predict hepatocellular carcinoma with deep sequencing and machine learning[J]. J Infect Dis, 2021, 223(11):1887-1896. DOI PMID
[24]	YANG Z, ZHANG H, YIN M, et al. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways[J]. Int J Biol Sci, 2022, 18(15):5963-5977. DOI PMID
[25]	LIU W, CAI S, PU R, et al. HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and upregulating inflammatory signaling[J]. Cancers(Basel), 2022, 14(13):3274.
[26]	WANG H, WANG A H, GRESSNER O A, et al. Association between HBV Pre-S mutations and the intracellular HBV DNAs in HBsAg-positive hepatocellular carcinoma in China[J]. Clin Exp Med, 2015, 15(4):483-491. DOI PMID
[27]	LEE I K, LEE S A, KIM H, et al. Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant[J]. World J Gastroenterol, 2015, 21(22):6872-6883.
[28]	YUAN S, SHE D, JIANG S, et al. Endoplasmic reticulum stress and therapeutic strategies in metabolic,neurodegenerative diseases and cancer[J]. Mol Med, 2024, 30(1):40.
[29]	AN Y, WANG X, GUAN X, et al. Endoplasmic reticulum stress-mediated cell death in cardiovascular disease[J]. Cell Stress Chaperones, 2024, 29(1):158-174.
[30]	WANG Y, DENG B. Hepatocellular carcinoma:molecular mechanism,targeted therapy,and biomarkers[J]. Cancer Metastasis Rev, 2023, 42(3):629-652.
[31]	CAO H, ZHOU X, XU B, et al. Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells[J]. J Zhejiang Univ Sci B, 2024, 25(3):212-232.
[32]	SHREYA S, GROSSET C F, JAIN B P. Unfolded protein response signaling in liver disorders:a 2023 updated review[J]. Int J Mol Sci, 2023, 24(18):14066.
[33]	SHI W, CHEN J, ZHAO N, et al. Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome[J]. J Mol Cell Cardiol, 2024,186:81-93.
[34]	PAVLOVI N, CALITZ C, THANAPIROM K, et al. Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma[J]. Elife, 2020,9:e55865.
[35]	HSU H T, LIN Y M, HSING M T, et al. Correlation between low cytoplasmic expression of XBP1 and the likelihood of surviving hepatocellular carcinoma[J]. In Vivo, 2024, 38(3):1316-1324.
[36]	LU H J, KOJU N, SHENG R. Mammalian integrated stress responses in stressed organelles and their functions[J]. Acta Pharmacol Sin, 2024, 45(6):1095-1114.
[37]	ZHOU B, LU Q, LIU J, et al. Melatonin increases the sensitivity of hepatocellular carcinoma to sorafenib through the PERK-ATF4-Beclin1 pathway[J]. Int J Biol Sci, 2019, 15(9):1905-1920. DOI PMID

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]