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editorial
. 2020 Jun 20;28(6):466–470. [Article in Chinese] doi: 10.3760/cma.j.cn501113-20200311-00107

癌胚型特异标志物与肝癌免疫治疗

Carcinoembryonic type specific markers and liver cancer immunotherapy

Yao Min 1,#, Yang Junling 2, Wang Li 3,通信作者：, Yao Dengfu 2,✉
Editor: 朱 红梅
PMCID: PMC12769621  PMID: 32660172

Abstract

Hepatocellular carcinoma (HCC) is a chronic inflammation derived from the background of hepatitis B and C virus (HBV and HCV) infection, chemicalintoxicants, or non-alcoholic fatty liver disease. Cancerous liver cells can express and secrete a variety of relatively specific markers, such as carcinoembryonic type of alpha-fetoprotein (AFP), phosphatidylinositol-3 (Glypican-3, GPC-3), Wnt/β-Catenin key molecule of signaling pathway Wnt3a and liver cancer specific GGT-Ⅱ (HS-GGT), etc. Clinical analysis of carcinoembryonic markers not only contributes to diagnosis and prognosis of HCC, but may also be the target of HCC immunotherapy with a promising prospect of development and application. This article reviews the latest valuable advances in carcinoembryonic type specific molecular markers and liver cancerimmunotherapy.

Keywords: Hepatocellular carcinoma, Immunotherapy, Specific biomarkers

肝细胞肝癌（hepatocellular carcinoma,HCC）的预防、早期诊断及精准治疗，仍是医学急需攻克的难题[1,2]。肝炎病毒（HBV、HCV）的慢性持续性感染、化学致癌物摄入和非酒精性脂肪性肝病等与HCC发生密切相关。癌基因或癌相关基因激活、抗癌基因失活或胚胎期癌相关基因的重新活化等，均可诱发肝细胞发生恶性转化，在多阶段进展过程中表达并分泌多种特异标志物[3]。肝癌治疗仍以手术为主、非手术为辅（血管栓塞、射频、放化疗和生物治疗等），虽有效地切除局部病灶，但术后复发率高，预后差[4,5]。多重激酶抑制剂索拉非尼虽能延长HCC患者中位生存期，但其疗效仍不理想[6]。积累的资料显示，肝癌组织表达与分泌的特异性抗原、相关通路关键分子、生长因子及受体和癌基因产物等可作为治疗靶点，癌胚型抗原介导的治疗靶点具高度特异性，可能在HCC治疗中具有应用前景。本文评述了癌胚型特异分子及其所介导的免疫治疗的研究进展。

1.基于甲胎蛋白（alpha fetoprotein,AFP）的免疫治疗：胎肝合成的AFP糖蛋白，由609个氨基酸单链多肽组成，含有位于氨基端（N端）3个结构域的24个氨基酸残基的前导信号点（9～10个aa）[7]。人体主要组织相容性复合物（major histocompatibility complex，MHC）Ⅰ或Ⅱ类分子可识别这些前导信号，再递呈给CD4+和CD8+T淋巴细胞，活化后的T淋巴细胞能识别机体的免疫显性抗原（immuno dominant）和亚免疫显性抗原（sub-dominant）表位。人类AFP抗原表位氨基酸肽链序列与免疫源性见表1。免疫或亚免疫源性AFP肽链，在人体内发挥免疫调节作用，具有多肽疫苗作用，可诱导和激发人体抗AFP特异性免疫反应[8]。

表1. 甲胎蛋白抗原表位氨基酸序列与免疫源性.

序号 甲胎蛋白肽链起点 氨基酸数 氨基酸肽链片段 免疫源性
1 7 9 IFLIFLLNF 亚免疫显性抗原
2 137 9 PLFQVPEPV 免疫显性抗原
3 150 9 AYEEDRETF 亚免疫显性抗原
4 158 9 FMNKFIYEI 免疫显性抗原
5 218 9 LLNQHACAV 亚免疫显性抗原
6 235 9 FQAITVTKL 亚免疫显性抗原
7 249 10 KVNFTEIQKL 免疫显性抗原
8 307 9 TTLERGQCII 亚免疫显性抗原
9 321 9 KPEGLSPNL 免疫显性抗原
10 325 10 GLSPNLNRFL 免疫显性抗原
11 357 9 EYSRRHPQL 免疫显性抗原
12 364 10 QLAVSVILRV 免疫显性抗原
13 403 9 KYIQESQAL 免疫显性抗原
14 414 9 RSCGLFQKL 免疫显性抗原
15 424 9 EYYLQNAFL 免疫显性抗原
16 434 9 AYTKKAPQL 免疫显性抗原
17 485 10 CIRHEMTPV 亚免疫显性抗原
18 492 9 PVNPGVGQC 亚免疫显性抗原
19 503 9 SYANRRPCF 亚免疫显性抗原
20 507 10 NRRPCFSSLV 亚免疫显性抗原
21 542 9 GVALQTMKQ 免疫显性抗原
22 547 10 TMKQEFLINL 亚免疫显性抗原
23 555 9 NLVKQKPQI 亚免疫显性抗原
24 591 9 CFAEEGQKL 亚免疫显性抗原
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AFP肽链有多个片段显现免疫显性及亚免疫显性表位，均能被MHC-Ⅰ类分子识别，特异诱导T淋巴细胞活化，识别AFP抗原。AFP阳性外周血单核细胞（peripheral blood mononuclear cell, PBMC）含5种人类白细胞抗原（human lymphocyte antigen,HLA）-A*24：02限制性T淋巴细胞表位，源于AFP衍生肽诱导细胞毒性T淋巴细胞（cytotoxic T lymphocyte,CTL）产生的干扰素γ可杀死AFP阳性肝癌细胞。其虽已临床试验，但树突状细胞（dendritic cell,DC）功能、特异性CTL、CD8+T淋巴细胞反应和AFP-HCC靶向治疗等仍待研究[9]。经体外诱导和筛选制备的T淋巴细胞受体（T cell receptor,TCR），可特异性识别和结合AFP/HLA-A*02+于AFP158-166肽FMNKFIYEI，为肝癌免疫治疗奠定基础[10]。

肝癌患者HLA-A*24：02比HLA-A*02:01常见，对Hep G2细胞HLA结合肽质谱发现，HLA-A*24：02限制性肽KWVESIFLIF（AFP2-11信号），健康者PBMC AFP2-11-HLA-A*24:02特异TCR（KWV3.1）为可溶性，转染T淋巴细胞能特异性激活并杀伤AFP+含AFP2-11的T2-A24细胞及AFP+HLA-A*24：02+癌细胞，提示AFP+HLA-A*24：02+抗原为HCC免疫治疗新靶点[10]。联合应用抗细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen 4,CTLA4）治疗（tremelimumab）和局部治疗，经PBMC及生存分析其有效率为26%[11]。抗CTLA4治疗后，血CD4+-HLA-DR+、CD4+PD-1+、CD8+HLA-DR+、CD8+PD-1+、CD4+ICOS+和CD8+ICOS+T淋巴细胞增加，CD4+PD-1+细胞高者对抗CTLA4治疗较好。经抗CTLA4处理后，AFP和Survivin特异性CD8+T淋巴细胞程序性死亡受体（programmed death,PD）-1表达增加，浸润性CD3+T淋巴细胞也增加。以抗CTLA4治疗后T淋巴细胞活化，表明抗CTLA4联合消融，使CD8+T淋巴细胞增加，患者HCV载量减少，为潜在的晚期肝癌患者治疗新方法[12]。

2.基于HBV基因的免疫治疗：HBV感染分为免疫耐受期、免疫清除期、非活动复制期和再活动期；当机体免疫力低下或劳累时，均可诱导HBV基因变异[13,14]。在HBV基因型A、B、C、D、E、F、G和H中，我国肝癌患者以病毒C、B型为主，且C型占74.5%。C型中C2亚型比B型更易诱发癌变，术后易复发[15,16]。HBV相关肝癌含不编码HBV抗原的短小HBV DNA片段，可利用该DNA整合HCC患者基因组使HBV转录组产生特异性TCR识别抗原决定簇进行T淋巴细胞免疫治疗。其方法是在体外以电穿孔方式将TCR基因转导至患者自体T淋巴细胞使其表达TCR，再将TCR阳性T淋巴细胞（每周1×104～10×106/kg，连续112d或1年）输给患者，该细胞含短HBV DNA编码的T淋巴细胞识别及激活的抗原表位，可用于肝癌个体化T淋巴细胞治疗，已有数例初步验证HBV特异性T淋巴细胞疗效及作用，期待更多病例验证[17]。

HBV感染极易慢性化，其后天免疫系统由免疫耐受转变为逐渐增强的免疫激活、失活、再激活和衰竭，导致HCC发生。慢性乙型肝炎HBx基因可与肝细胞基因19q12、2q32.2和22q12位点整合，将HBx基因转染至肝癌Hep G2细胞后，第3、18、20号染色体发生改变微核数增加3倍；HBx蛋白可调节胞内基因、结合转录因子、激活相关通路与启动子，诱导细胞恶性转化[18,19]。以抗HBx Ag单克隆抗体（188Re-anti-HBx）治疗HBV相关肝癌，或用表达HBx Ag的Hep3B2.1-7细胞制作移植瘤模型，经188Re-4H9单克隆抗体治疗后均见癌组织188Re-4H9特异聚集，瘤体缩小并呈剂量依赖性。病理学见瘤内坏死、出血程度加重。因核素标记抗HBx靶点是癌细胞或病毒感染细胞表面抗原，而非体内自身抗原，与核素标记单克隆抗体相比，更特异、毒性低，显示单克隆抗体结合HBx抗原除治疗HCC外，可在HBV持续感染的非癌变期发挥抑制作用[20,21]。

3.基于癌胚型磷脂酰肌醇蛋白多糖-3（glypican-3, GPC-3）的免疫治疗：GPC-3为癌胚型糖蛋白，位于Wnt通路上游仅在HCC过表达，且与HBV感染相关。GPC-3作为新生标志物已用于HCC诊断与鉴别诊断，同时也是HCC免疫治疗新靶点[22,23]，已证明或正在应用GPC-3作为肝癌免疫治疗的分子靶点见表2。抗GPC-3单克隆抗体（h GC33）可诱导GPC-3阳性癌细胞产生抗体依赖性细胞介导的细胞毒作用，对Huh-7和Hep G2细胞移植瘤有明显抑制作用；以h GC33治疗可抑制癌细胞增殖，使癌细胞合成AFP下降；将h GC33与索拉非尼联合使用，可有效抑制肝癌的生长[24]。

表2. GPC-3作为肝癌免疫治疗的分子靶点.

类别 名称 种属 抗原表位 正在验证/应用
抗体 M18D04/19B11 小鼠 N-末端（aa：25-358） 基础研究
A1836A 小鼠 N-末端 基础研究
GPC3-C02 小鼠 C-末端 基础研究
GC33 小鼠 C-末端（aa：524-563） 临床前/基础研究
hGC33 人GC33 C-末端（aa：524-563） Ⅱ期临床试验
HS20 人 硫酸乙酰肝素链 临床前试验
sGPC-3 人 - 临床前试验
疫苗 GPC-3298-306 小鼠 298-306肽 Ⅱ期临床试验
GPC-3144-152 小鼠 144-152肽 Ⅱ期临床试验
miRNA miR-219-5p 人 - 体内、外研究
miR-520c-3p 人 - 体外研究
miR-1271 人 - 体外研究
shRNA GPC-3 shRNA 人 - 体内、外研究
siRNA GPC-3 siRNA 人 - 体内、外研究
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注：GPC-3：磷脂酰肌醇蛋白多糖-3；-：无

正常肝细胞或良性肝病中未见GPC-3表达，GPC-3对肝癌具特异性免疫源性，可用于肝癌精准治疗，动物模型和体外研究均已证明[25,26]。因肝癌特异表达GPC-3，与硫酯酶-2和Wnt3a信号异常呈正相关，GPC-3调控下游Wnt/β-catenin通路相关分子。以RNAi沉默GPC-3可显著抑制肝癌细胞增殖和侵袭，瘤体衰减；癌组织GPC-3表达，常伴胞核/胞质β-catenin增高；抑制GPC-3可下调基质金属蛋白酶（matrix metalloproteinase,MMP）表达[27]。GPC-3异常表达可经Wnt/β-catenin通路诱导癌细胞增殖等。针对GPC-3免疫疗法已开发，包括GPC-3疫苗、抗GPC-3免疫毒素和嵌合抗原受体修饰细胞。以GPC-3转染修饰DCs激活人T淋巴细胞介导免疫反应，抑制癌细胞增殖、转移，GPC-3转染DCs对癌细胞具细胞毒性，如p EF-h GPC3质粒转染DCs刺激效应细胞溶解癌细胞，可为HCC新疫苗。针对GPC-3调控Wnt信号抑制HCC生长，可作为HCC治疗新方案[28,29]。

4.基于关键信号分子Wnt3a治疗：HBV和HCV感染均可激活Wnt/β-catenin信号通路，参与肝癌进展[30]。HBx可活化Src激酶抑制糖原合成酶3β活性导致胞内β-catenin积聚；HBx促进DNA甲基转移酶1和Wnt3a表达，与分泌型卷曲蛋白（secreted frizzled related protein,SFRP）1、5结合，使SFRP1和SFRP5沉默；HBx可减轻去乙酰化酶1对β-catenin的抑制以激活Wnt通路促进HCC进展[31,32]；HCV核心蛋白可诱导癌细胞Wnt3a表达、T淋巴细胞因子依赖转录、抑制癌细胞糖原合成酶3β、增加和稳定胞内β-catenin向核内转运，调控下游cyclin D1、c-myc、WISP2及结缔组织生长因子等靶基因表达；也可诱导Wnt3a表达，上调癌细胞Wnt1和WISP2表达，促进癌细胞增殖、DNA合成等[33,34]，提示抑制Wnt3a可上调SIRT1表达，有可能是HBV或HCV相关HCC治疗的又一新策略。

尽管Wnt3a活化是HCC特异诊断及预后判断标志物[35]，其也可能是HCC免疫治疗的靶目标。Crispr/cas9技术靶向精确性高，载体构建周期短，无物种限制等优点，在基因和蛋白水平，以Crispr/cas9-sg RNA慢病毒载体系统成功干预肝癌细胞Wnt3a基因转录，体内、外研究结果已证实其对癌细胞增殖和移植瘤生长的抑制作用；在细胞水平的研究显示，干预Wnt3a转录或敲除Wnt3a基因均可明显抑制下游β-catenin信号分子表达；移植瘤模型证实敲除Hep G2细胞中Wnt3a基因，肝癌移植瘤生长缓慢、瘤体显著减小、瘤质量显著减轻。Wnt通路是涉及多靶点的级联反应途径，阻断上游的GPC-3、Wnt3a及下游β-catenin，可多靶点阻断Wnt信号通路激活，进而抑制HCC发生或延缓HCC进展，为HCC治疗提供新的依据，可见肝癌细胞的Wnt3a和β-catenin过表达，有望成为抑制HCC生长的新靶点[36]。

5.基于分泌型丛生蛋白靶向治疗：存在于高尔基体的分泌型丛生蛋白（secretory clusterin, sCLU）是一种应激诱导的异源二聚体硫酸化糖蛋白，其基因定位于8p21～p12。基础和临床研究显示正常肝组织s CLU低表达，肝细胞恶性转化时s CLU呈进行性过表达，与HCC进展密切相关[37]。人肝癌组织或循环血s CLU均过表达，免疫组织化学显示Ⅰ期癌组织s CLU阳性率73.3%，无论m RNA还是蛋白水平均随临床分期逐渐升高，是鉴别良、恶性肝病的标志物。肝癌术后复发和转移是预后不良的主要原因，s CLU在癌细胞增殖、多药耐药（multiple drug resistance,MDR）、浸润和转移中起作用[38]。对BEL-7402和SMMC-7721细胞研究显示，s CLU介导MMP-2、p-AKT和E-cadherin等表达，下调s CLU可减少癌细胞侵袭，相反s CLU过表达则增加癌细胞侵袭能力[39]。可见s CLU为肿瘤侵袭分子，参与选择性环氧合酶-2抑制剂美洛昔康诱导的癌细胞增殖和侵袭，美洛昔康联合s CLU-sh RNA下调s CLU和p-AKT表达，也可降低癌细胞侵袭力，提示s CLU是肝癌发生、侵袭和转移的有效靶点，在免疫治疗方面具有开发前景[40]。

6.展望：综上所述，肝癌多基因变异伴DNA甲基化改变、microRNA、Inc RNA及免疫应答等。针对肝癌特异分子的免疫治疗，可望与手术、放化疗、介入等治疗方式联合应用，综合干预有助于改善疗效、延长患者生存时间。随着基因组学、蛋白质组学发展，分子病理、药理学及基因工程技术进步，经分子剪接、沉默、干预和单克隆抗体等技术，可直接封闭癌细胞生长相关信号分子或将其作为放射性核素、药物载体和免疫治疗等分子靶目标，期待更多、更特异、不良反应更少的免疫技术在肝癌精准或综合治疗中发挥独特作用。

作者贡献声明

姚敏、杨君伶：文献收集与论文撰写；王理、姚登福：指导与审阅

利益冲突

所有作者均声明不存在利益冲突

Funding Statement

基金项目：国家自然科学基金面上项目（31872738、81873915、81673241）

Fund program: National Natural Science Foundation(31872738,81873915,81673241)

参考文献

  • [1].Doycheva I, Thuluvath PJ. Systemic therapy for advanced hepatocellular carcinoma: an update of a rapidly evolving field[J].J Clin Exp Hepatol, 2019,9(5):588-596. DOI: 10.1016/j.jceh.2019.07.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Chen JG, Zhu J, Zhang YH, et al. Cancer survival in Qidong between 1972 and 2011: a population-based analysis[J].Mol Clin Oncol, 2017,6(6):944-954. DOI: 10.3892/mco.2017.1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Andrea CG, Giulia O, Francesco C, et al. Developments in predictive biomarkers for hepato- cellular carcinoma therapy[J].Expert Rev Anticancer Ther, 2020,20(1):63-67. DOI: 10.1080/14737140.2020.1712198. [DOI] [PubMed] [Google Scholar]
  • [4].Reig M, da Fonseca LG, Faivre S. New trials and results in systemic treatment of HCC[J].J Hepatol, 2018,69(2):525-533. DOI: 10.1016/j.jhep.2018.03.028 [DOI] [PubMed] [Google Scholar]
  • [5].Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma[J].Gastroenterology, 2016,150(4):835-853. DOI: 10.1053/j.gastro.2015.12.041. [DOI] [PubMed] [Google Scholar]
  • [6].Xia S, Pan Y, Liang Y, et al. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma[J].EbioMedicine, 2020,51:102610. DOI: 10.1016/j.ebiom.2019.102610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Li XJ, Shao DH, He ML, et al. Association of common variants in HNF1A gene with serum AFP level in healthy Chinese individuals and HCC patients[J].Dis Markers, 2019,2019:6273497. DOI: 10.1155/2019/6273497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Tai D, Choo SP, Chew V. Rationale of immunotherapy in hepatocellular carcinoma and its potential biomarkers[J].Cancers, 2019,11(12):1926. DOI: 10.3390/cancers11121926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Docta RY, Ferronha T, Sanderson JP, et al. Tuning T-cell receptor affinity to optimize clinical risk-benefit when targeting alpha-fetoprotein-positive liver cancer[J].Hepatology, 2019,69(5):2061-2075. DOI: 10.1002/hep.30477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Li Z, Gong H, Liu Q, et al. Identification of an HLA-A*24: 02-restricted α-fetoprotein signal peptide-derived antigen and its specific T-cell receptor for T-cell immunotherapy[J].Immunology, 2019,159(4):384-392. DOI: 10.1111/imm.13168. [DOI] [Google Scholar]
  • [11].Agdashian D, ElGindi M, Xie C, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma[J].Cancer Immunol Immunother, 2019,68(4):599-608. DOI: 10.1007/s00262-019-02299-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma[J].J Hepatol, 2017,66(3):545-551. DOI: 10.1016/j.jhep.2016.10.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Ren F, Li W, Xiang A, et al. Distribution and difference of APOBEC-induced mutations in the TpCpW context of HBV DNA between HCC and non-HCC[J].J Med Virol, 2020,92(1):53-61. DOI: 10.1002/jmv.25572. [DOI] [PubMed] [Google Scholar]
  • [14].Jin Y, Lee WY, Toh ST, et al. Comprehensive analysis of transcriptome profiles in hepatocellular carcinoma[J].J Transl Med, 2019,17(1):273. DOI: 10.1186/s12967-019-2025-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Du Y, Han X, Ding YB, et al. Prediction and prophylaxis of hepatocellular carcinoma occurrence and postoperative recurrence in chronic hepatitis B virus-infected subjects[J].World J Gastroenterol, 2016,22(29):6565-6572. DOI: 10.3748/wjg.v22.i29.6565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Yang F, Ma L, Yang Y, et al. Contribution of hepatitis B virus infection to the aggressiveness of primary liver cancer: a clinical epidemiological study in Eastern China[J].Front Oncol, 2019,9:370. DOI: 10.3389/fonc.2019.00370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy[J].Gastroenterology, 2019,156(6):1862-1876. DOI: 10.1053/j.gastro.2019.01.251. [DOI] [PubMed] [Google Scholar]
  • [18].Chaturvedi VK, Singh A, Dubey SK, et al. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma[J].Microb Pathog, 2019,128:184-194. DOI: 10.1016/j.micpath.2019.01.004. [DOI] [PubMed] [Google Scholar]
  • [19].Chen Y, Tian Z. HBV-induced immune imbalance in the development of HCC[J].Front Immunol, 2019,10:2048. DOI: 10.3389/fimmu.2019.02048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Huang P, Zhuang B, Zhang H, et al. Hepatitis B virus X protein (HBx) is responsible for resistance to targeted therapies in hepatocellular carcinoma: Ex vivo culture evidence[J].Clin Cancer Res, 2015,21(19):4420-4430. DOI: 10.1158/1078-0432.CCR-14-2067. [DOI] [PubMed] [Google Scholar]
  • [21].Liu H, Lou G, Li C, et al. HBx inhibits CYP2E1 gene expression via down- regulating HNF4 in human hepatoma cells[J].PLoS One, 2014,9:e107913. DOI: 10.1371/journal.pone.0107913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Ge S, Wang D, Lv B, et al. HCRP1, ID4 and Glypican-3: an optimal panel of biomarkers for diagnosis of hepatocellular carcinoma[J].Int J Clin Exp Pathol, 2018,11(12):5774-5782. [PMC free article] [PubMed] [Google Scholar]
  • [23].Cao W, Sharma M, Imam R, et al. Study on diagnostic values of astrocyte elevated gene 1 (AEG-1) and glypican 3 (GPC-3) in hepatocellular carcinoma[J].Am J Clin Pathol, 2019,152(5):647-655. DOI: 10.1093/ajcp/aqz086. [DOI] [PubMed] [Google Scholar]
  • [24].Wu Y, Liu H, Ding H. GPC-3 in hepatocellular carcinoma: current perspectives[J].J Hepatocell Carcinoma, 2016,3(1):63-67. DOI: 10.2147/JHC.S116513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Wu B, Shang H, Liang X, Preparation of novel targeting nanobubbles conjugated with small interfering RNA for concurrent molecular imaging and gene therapy in vivo[J].FASEB J, 2019,33(12):14129-14136. DOI: 10.1096/fj.201900716RR. [DOI] [PubMed] [Google Scholar]
  • [26].Yao M, Wang L, Fang M, et al. Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma[J].Biosci Trends, 2016,10(5):337-343. DOI: 10.5582/bst.2016.01176. [DOI] [PubMed] [Google Scholar]
  • [27].Dong Z, Yao M, Wang L, et al. Down-regulating glypican-3 expression: molecular- targeted therapy for hepatocellular carcinoma[J].Mini Rev Med Chem, 2014,14(14):1183-1193. DOI: 10.2174/1389557515666150101105135. [DOI] [PubMed] [Google Scholar]
  • [28].O'Beirne J, Farzaneh F, Harrison PM. Generation of functional CD8+ T cells by human dendritic cells expressing glypican-3 epitopes[J].J Exp Clin Cancer Res, 2010,29(1):48. DOI: 10.1186/1756-9966-29-48 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Guo M, Zhang HL, Zheng JM, et al. Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma[J].J Cancer, 2020,11(8):2008-2021. DOI: 10.7150/jca.39972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Petruzziello A. Epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma[J].Open Virol J, 2018,12(1):26-32. DOI: 10.2174/1874357901812010026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].von Olshausen G, Quasdorff M, Bester R, et al. Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion[J].Oncotarget, 2018,9(74):33947-33960. DOI: 10.18632/oncotarget.26103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Lin X, Zuo S, Luo R, et al. HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma[J].Theranostics, 2019,9(25):7583-7598. DOI: 10.7150/thno.37717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Aicher S, Kakkanas A, Cohen L, et al. Differential regulation of the Wnt/β-catenin pathway by hepatitis C virus recombinants expressing core from various genotypes[J].Sci Rep, 2018,8(1):1185. DOI: 10.1038/s41598-018-29078-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Mahmoudvand S, Shokri S, Taherkhani R, et al. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma[J].World J Gastroenterol, 2019,25(1):42-58. DOI: 10.3748/wjg.v25.i1.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Pan LH, Yao M, Cai Y, et al. Oncogenic Wnt3a expression as an estimable prognostic marker for hepatocellular carcinoma[J].World J Gastroenterol, 2016,22(14):3829-3836. DOI: 10.3748/wjg.v22.i14.3829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Zheng WJ, Yao M, Fang M, et al. Oncogenic Wnt3a:a candidate specific marker and novel molecular target for hepatocellular carcinoma[J].J Cancer, 2019,10(23):5862-5873. DOI: 10.7150/jca.31599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Yao M, Fang M, Zheng W, et al. Role of secretory clusterin in hepato- carcinogenesis[J].Transl Gastroenterol Hepatol, 2018,3(1):48. DOI: 10.21037/tgh.2018.07.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Zheng W, Yao M, Qian Q, et al. Oncogenic secretory clusterin in hepatocellular carcinoma: expression at early staging and emerging molecular target[J].Oncotarget, 2016,8(32):52321-52332. DOI: 10.18632/oncotarget.13674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Zheng W, Yao M, Wu M, et al. Secretory clusterin promotes hepatocellular carcinoma progression by facilitating cancer stem cell properties via AKT/GSK-3β/β-catenin axis[J].J Transl Med, 2020,18(1):81. DOI: 10.1186/s12967-020-02262-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Yao M, Sai W, Zheng W, et al. Secretory clusterin as a novel molecular-targeted for inhibiting hepatocellular carcinoma growth[J].Curr Med Chem, 2019. DOI: 10.2174/0929867326666190624161158. [DOI] [Google Scholar]

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