对HBV preS / S突变的临床意义以及preS2缺失对线粒体，肝纤维化

StephenW

Clinical implications on HBV preS/S mutations and the effects of preS2 deletion on mitochondria, liver fibrosis, and cancer development
Yuh-Jin Liang  1   2 , Wei Teng  3   4 , Chih-Li Chen  5 , Cheng-Pu Sun  6 , Rui-Dung Teng  4 , Yen-Hua Huang  7 , Kung-Hao Liang  1 , Yi-Wen Chen  1 , Chung-Chih Lin  8 , Chien-Wei Su  9   10 , Mi-Hua Tao  5 , Jaw-Ching Wu  1   4   2
Affiliations
Affiliations

    1
    Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taiwan, ROC, Taipei.
    2
    Cancer Progression Research Center, National Yang-Ming University, Taiwan, ROC, Taipei.
    3
    Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC.
    4
    Institute of Clinical Medicine, National Yang-Ming University, Taiwan, ROC, Taipei.
    5
    School of Medicine, College of Medicine, Fu Jen Catholic University, Taiwan, ROC, Taipei.
    6
    Institute of Biomedical Sciences, Academia Sinica, Taiwan, ROC, Taipei.
    7
    Center for Systems and Synthetic Biology and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan, ROC.
    8
    Department of Life Sciences and Institute of Genome Sciences, Yang-Ming University, Taiwan, ROC.
    9
    Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC, Taipei.
    10
    Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan, ROC, Taipei.

    PMID: 33675094 DOI: 10.1002/hep.31789

Abstract

Background & aims: PreS mutants of HBV have been reported to be associated with hepatocellular carcinoma (HCC). We conducted a longitudinal study of the role of HBV preS mutations on development of HCC, particularly in chronic hepatitis B (CHB) patients having low HBV DNA or ALT levels, and investigated effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo.

Approach and results: Association of preS mutations with HCC in 343 CHB patients was evaluated by retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, ER stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed significant association of preS mutations with HCC (HR: 3.210, 95% CI: 1.072-9.613; p=0.037) including cases with low HBV DNA or ALT levels (HR: 2.790, 95% CI: 1.133-6.873; p=0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. preS2ΔMT expression promoted HBsAg retention in ER and unfolded protein response (UPR). TEM examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected hu-FRG mice than in WT HBV-infected mice. preS2ΔMT-infected mice displayed upregulation of UPR and caspase-3, and enhanced liver fibrosis.

Conclusions: PreS mutations were significantly associated with HCC development in CHB patients, including those low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in CHB patients, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.

Keywords: calcium homeostasis; hu-FRG mice; humanized liver chimeric mice; preS2 deletion mutation.

This article is protected by copyright. All rights reserved.

StephenW

对HBV preS / S突变的临床意义以及preS2缺失对线粒体，肝纤维化和癌症发展的影响
梁玉珍1 2，滕伟3 4，陈志立5，孙承璞6，滕瑞栋4，黄恩华7，梁公豪1，陈以文1，忠忠林志豪8，苏建伟9 10，陶蜜华5，吴乔成1 4 2
隶属关系
隶属关系

    1个
    台湾中华民国台北市荣民总医院医学研究部转化研究室。
    2个
    国立阳明大学癌症进展研究中心，台湾中华民国台北。
    3
    中华民国台湾省林口市长庚纪念医院消化内科。
    4
    国立阳明大学临床医学研究所，台湾中华民国台北。
    5
    台湾中华民国辅仁大学医学院医学院。
    6
    中国台湾省中央研究院生物医学科学研究所，台北。
    7
    国立阳明大学系统与合成生物学中心和生物医学信息学研究所，台湾台北。
    8
    台湾阳明大学生命科学系和基因组科学研究所，台湾。
    9
    台湾中华民国台北市荣民总医院消化内科。
    10
    国立阳明大学医学院医学院，中华民国台北。

    PMID：33675094 DOI：10.1002 / hep.31789

抽象的

背景与目的：据报道，HBV的PreS突变体与肝细胞癌（HCC）相关。我们对HBV preS突变在HCC发生中的作用进行了纵向研究，尤其是在HBV DNA或ALT水平较低的慢性乙型肝炎（CHB）患者中，并研究了分泌缺陷型preS2缺失突变体（preS2ΔMT）对肝细胞损伤的影响。体外和体内肝纤维化。

方法和结果：343例CHB患者中preS突变与HCC的关联通过回顾性病例对照随访研究进行评估。检查了preS2ΔMT对HBsAg保留，内质网应激，钙积累，线粒体功能障碍和肝纤维化的影响。多变量分析显示preS突变与HCC显着相关（HR：3.210，95％CI：1.072-9.613; p = 0.037），包括HBV DNA或ALT水平低的病例（HR：2.790，95％CI：1.133-6.873; p = 0.026）。抗病毒治疗降低了HCC风险，包括具有preS突变的病例。 preS2ΔMT表达促进ERs中的HBsAg保留和未折叠的蛋白应答（UPR）。 TEM检查，MitoTracker染色，实时ATP测定以及表达preS2ΔMT的细胞的钙染色显示ER和线粒体超微结构异常，线粒体膜电位和ATP产生减少以及钙超载。 preS2ΔMT感染的hu-FRG小鼠的血清HBV分泌水平比WT HBV感染的小鼠低约100倍。被preS2ΔMT感染的小鼠显示出UPR和caspase-3的上调，并增强了肝纤维化。

结论：PreS突变与CHB患者的HCC发生显着相关，包括那些低HBV DNA或ALT水平的患者。抗病毒治疗减少了CHB患者（包括具有preS突变的患者）的HCC发生。突变的HBsAg的细胞内蓄积诱导或促进ER应激，钙超载，线粒体功能障碍，能量代谢受损，肝纤维化和HCC。

关键字：钙稳态； hu-FRG小鼠人源化肝嵌合体小鼠； preS2缺失突变。

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