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. 2023 Feb 28;48(2):260–267. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220042

MAGE-A家族在胃癌中作用的研究进展

Research progress in effects of MAGE-A family on gastric cancer

JIA Qi 1,2, XIAN Xiaohong 1, LI Yangrun 1, MU Jiaxin 1, DU Zhixing 1,✉
Editor: 彭 敏宁
PMCID: PMC10930336  PMID: 36999473

Abstract

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and most of the patients are diagnosed at the advanced stage. Most of the treating options are comprehensive treatment, in which immunotherapy plays more and more important role. Melanoma antigen-associated gene-A (MAGE-A) family is a kind of cancer testis antigens. Except in germ cells of testis and trophoblast cells of placenta, MAGE-A family is highly expressed in cancerous tissues and participates in a variety of biological processes, such as cancer cell proliferation, differentiation and metastasis. In addition, cancer testis antigen also possesses good immunogenicity, which can induce humoral and cellular immune responses, is a good target for immunotherapy, and has good application value in the diagnosis, treatment and prognosis of GC. A variety of targeted therapeutic drugs based on MAGE-A are in phase I or II clinical trials, it has good safety and potential clinical application value. With the continuous progress of clinical trials and basic research on MAGE-A targets in GC, it is expected to provide a theoretical basis for clinical transformation and immunotherapy of MAGE-A in the future.

Keywords: melanoma antigen-associated gene-A family, gastric cancer, immunotherapy, therapeutic targets

胃癌(gastric cancer，GC)现为全世界发病率第5位，病死率第4位的恶性肿瘤，严重威胁人类健康。根据2020年全球癌症流行病学统计[1]，全球新增GC患者108万例，死亡76.9万例。目前超过70%的GC患者诊断时已为晚期，手术、化学治疗(以下简称化疗)疗效都不太理想。近年来，免疫治疗成为GC治疗的新的关注点和突破点，但实体肿瘤的免疫治疗尚处于起步阶段，目前免疫检查点抑制剂(immune checkpoint inhibitors，ICIs)程序性细胞死亡1(programmed cell death 1，PD-1)和程序性死亡配体1(programmed death-ligand 1，PD-L1)通路中的靶向免疫治疗成为实体瘤治疗的突破点，临床试验已证实其有效性，并且联合化疗在GC新辅助治疗中效果显著。尽管现有免疫治疗已被批准作为晚期GC的三线治疗方案，但其治疗有效率并不高，患者无进展生存期较短，临床治疗需求未被满足，真正对GC患者有转机作用的免疫药物尚未发现，仍缺乏高特异度的免疫治疗靶点[2-4]。目前认为免疫治疗的有效性和不良反应很大程度上取决于特异性靶点的选择，因此发掘有效且特异性较强的分子靶点是推动该领域发展的重要方向。

黑色素瘤相关抗原基因-A(melanoma antigen-associated gene-A，MAGE-A)家族是一类特异性的免疫治疗靶点，属于癌/睾丸抗原基因家族，除在睾丸或胎盘中高表达外，还在癌变组织中高表达，而在其他正常组织中不表达或低表达，是一种较理想的肿瘤免疫治疗靶点，具有很好的免疫原性，可诱导靶向细胞毒性T淋巴细胞引发抗肿瘤免疫，从而杀伤肿瘤细胞[5-7]。本文系统地归纳和总结了MAGE-A家族在GC中的功能、临床转化和应用的最新研究进展，为基于MAGE-A家族的免疫治疗奠定基础。

1. MAGE-A家族

1.1. MAGE-A家族的发现及组成

MAGE-A家族第1个成员首次于1991年由van der Bruggen等[8]通过 T 细胞表位克隆技术在MZ-2人黑色素瘤细胞系中被发现，现被命名为MAGE-A1。随着研究的不断深入，目前已经发现了MAGE-A家族中的12个成员，即MAGE-A1~12。

1.2. MAGE-A家族的特性

MAGE-A是一种具有高度特异性表达模式的肿瘤抗原，其表达具有以下特点：在组织表达限制性方面，MAGE-A高表达于正常组织的睾丸、胎盘及各类肿瘤(如黑色素瘤、食管癌、乳腺癌、肺癌和GC等)组织中[5-6, 9-10]。在免疫原性方面，可在患者体内引发自身体液免疫反应和诱导产生靶向细胞毒性T 淋巴细胞的特异性细胞免疫反应来杀伤肿瘤细胞，因此MAGE-A有望成为免疫治疗靶点的肿瘤抗原[5-7]。

由MAGE-A编码的MAGE蛋白因其仅激活主要组织相容性复合体(major histrocompatibility complex,MHC)-I类分子且具有引起强烈的细胞毒性T淋巴细胞(cytotoxic T cells，CTL)反应的良好抗原特性和局限表达于生殖细胞和癌细胞的独特表达模式，成为人们研究免疫治疗的理想靶标和癌症生物标志物的新方向。Kuldkepp等[11]研究表明至少有2个MAGE-A家族成员(MAGE-A4和MAGE-A10)编码蛋白质可整合到细胞释放的细胞外囊泡(extracellular vesicles，EV)中并暴露在释放的EV表面，从而与远处细胞进行通信，在促进癌症进展中发挥作用；并因癌细胞比正常人体细胞分泌更多的EV，从而可将EV和其携带的肿瘤相关分子作为癌症诊断的标志物。蔡一奇等[12]还利用原核细胞表达的MAGE-A3蛋白制备了MAGE-A3蛋白特异性兔多克隆抗体，可以特异性识别GC细胞中的MAGE-A3蛋白。此外，MAGE-A1和MAGE-A3 mRNA可以作为特异性的肿瘤标志物用来检测GC患者外周血中微转移的肿瘤细胞，阳性率达62.5%[13]。

目前基于MAGE-A基因的免疫疗法主要有肿瘤分子疫苗和T细胞转移疗法，其表现出很好的抗肿瘤性[14]，针对GC的MAGE-A家族免疫疗法的临床试验主要集中于MAGE-A3、MAGE-A4和MAGE-A6基因。

2. MAGE-A家族在GC中的表达及功能

多项研究[15-19]均已证实MAGE-A家族成员MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A10、MAGE-A12在GC组织中高表达，表达率为29%~80.5%。未见MAGE-A5、MAGE-A7、MAGE-A8、MAGE-A9、MAGE-A11在GC组织中表达的研究报道。

2.1. MAGE-A1

1994年，de Smet等[20]首次提出MAGE-A1在正常组织中的表达仅见于睾丸。随后研究[9]证实MAGE-A1在多种恶性肿瘤如黑色素瘤、胶质母细胞、神经母细胞瘤、非小细胞肺癌、喉癌、乳腺癌等中也有高表达。国外研究[15, 21]表明MAGE-A1在GC中的表达率为29%~32.6%，同时发现MAGE-A1的表达与GC的病理类型、血管侵犯、患者预后相关，然而多因素分析显示MAGE-A1并不是预测GC预后的独立分子指标；且高表达MAGE-A1的GC患者的淋巴转移率较高，临床分期较晚，预后较差。这提示MAGE-A1对GC的预后判断具有一定的价值。

He等[22]将Ad-MAGE-A1转导至树突状细胞(dendritic cell，DC)后生产了能刺激特异性T淋巴细胞的DC疫苗，该疫苗可以通过产生高水平的INF-γ特异性地杀伤GC细胞。目前基于MAGE-A1为靶点的DC疫苗为临床前研究，尚未开展临床转化研究，其临床特异性和有效性仍待进一步探索。

2.2. MAGE-A2

MAGE-A2除在生殖、未分化细胞、癌细胞及小鼠胚胎干细胞中特异性表达外[23]，还在于大多数精原细胞瘤、纯胚胎肿瘤及一半的纯卵黄囊肿瘤中表达[24]。研究[25]表明MAGE-A2过表达可使Akt和Erk1/2磷酸化而被激活，引起肿瘤细胞的显著增殖和转移。Park等[23]提出敲减MAGE-A2可诱导小鼠胚胎干细胞凋亡。这些研究均表明 MAGE-A2参与肿瘤的增殖和凋亡。

在GC组织中MAGE-A2基因的启动子表现为去甲基化状态，且MAGE-A2基因的表达与肿瘤的侵袭性、淋巴结转移和病理分期较晚密切相关[26]，提示MAGE-A2的表达与否对GC患者的预后具有预测价值。然而关于MAGE-A2的临床试验和转化研究未见相关报道。

2.3. MAGE-A3

研究[6]证实MAGE-A3基因在黑色素瘤、脑癌、乳腺癌、肺癌和卵巢癌等多种恶性肿瘤中表达。MAGE-A3在GC中的表达率为39.8%~66%[16-17, 21]。

基因甲基化水平与肿瘤生物学特性密切相关，癌基因DNA甲基化水平越低，其肿瘤浸润能力越强，组织越易发生癌变[27]。MAGE-A3基因启动子去甲基化会提高肿瘤细胞中MAGE-A3的表达，从而使细胞表型恶性转化，导致肿瘤的发生[28]。在66%(56/84例)的GC标本中，MAGE-A3的启动子发生去甲基化改变。与未去甲基化的患者相比，去甲基化患者发生淋巴结转移及较差预后的风险更高。并且已有研究[21]发现在进展期GC患者中MAGE-A3去甲基化水平更高，推测其去甲基化水平与GC的侵袭性生物学行为密切相关。对于MAGE-A3基因启动子甲基化状态的分析将有助于恶性肿瘤的诊断和预后判断。

MAGE-A3抗原含有MHC-I、II类分子限制性抗原表位，可被CD4+ T细胞和CD8+ T细胞所识别[29]，良好的免疫原性使它可作为肿瘤免疫治疗的靶抗原。由于MAGE-A3可引发机体产生体液和细胞免疫反应，因此临床试验中使用MAGE-A3疫苗诱导机体产生针对MAGE-A3的特异性免疫反应来杀伤肿瘤细胞[6]，目前相关免疫治疗的临床试验正在陆续开展中。

2.4. MAGE-A4

1995年，Imai等[30]首次通过RT-PCR和核苷酸测序的方法确定了MAGE-A4为1 064 bp的cDNA片段。Ishihara等[10]通过分析21种肿瘤类型的 585 个组织样本发现MAGE-A4基因在食管癌、头颈部癌、GC和卵巢癌中的表达率分别为54.9%、37.5%、35.0%和34.2%。MAGE-A4及其相关共表达基因主要富集于Notch信号通路，Notch通过与CSL(CBF-1，suppressor of hairless，Lag的合称)DNA结合蛋白和MAML(mastermind-like family members)在细胞核内形成转录因子复合体调节下游基因，使细胞凋亡和分化失控，导致肿瘤细胞无限扩增，形成恶性肿瘤[31]。

Werner等[32]在329名GC患者、321名健康者和124名上消化道其他疾病患者血清样本中发现5种肿瘤抗原的自身抗体组合(MAGE-A4、CTAG1、TP53、ERBB2_C、SDCCAG8)能够检出32%的GC患者，其特异度为87%。上述研究表明一些自身抗体，如抗MAGE-A4、抗CTAG1或抗TP53及其组合，与其他标志物结合时，可能有助于癌症的早期检测。

2.5. MAGE-A6

相比于其他MAGE-A家族成员，MAGE-A6在肿瘤早期病变中的表达率较高，为64%[18]。MAGE-A6也在浸润性乳腺癌、结肠腺癌和肺鳞状细胞癌等多种肿瘤细胞中显著高表达[33-35]。肿瘤抑制蛋白AMP活化蛋白激酶[adenosine 5'-monophosphate (AMP)-activated protein kinase，AMPK]是细胞能量的主要传感器和调节器。Pineda等[36]研究发现MAGE-A3/6-TRIM28 E3连接酶复合物可通过泛素化途径降解AMPKα1，导致细胞自噬的抑制、mTOR信号的激活以及AMPK激动剂(如二甲双胍)的超敏反应，从而使肿瘤发生。而有研究[35, 37-38]表明敲除MAGE-A6基因可以激活AMPK信号，从而抑制人肾细胞癌细胞、结肠直肠癌细胞、胶质瘤细胞的生长。Tsang等[39]在胰腺导管腺癌细胞模型中也发现MAGE-A6可抑制自噬，促进胰腺癌的发生、发展。上述研究表明MAGE-A6主要通过参与AMPK信号通路来影响肿瘤细胞的发生。

多项研究[40-41]证明DNA去甲基化可以通过MAGE-A6基因的转录激活途径来促进肿瘤的发生并增强CTL细胞对肿瘤细胞的识别。Endo等[42]发现MAGE-A6在GC组织中高表达，且与患者不良预后相关，同时还发现MAGE-A6蛋白有可能成为预测GC复发的指标。

2.6. MAGE-A10

MAGE-A10是MAGE-A家族中的高免疫原性成员，在黑色素瘤、膀胱癌、肺癌、食管癌和头颈部鳞癌中有较高的表达水平。其蛋白质为70 kD的核内蛋白质，在正常精原细胞和精母细胞中表达，但在其他正常组织中不表达[43]。Suzuki等[19]报道MAGE-A10在未发生转移GC中的表达率和发生肝转移GC中的表达率分别为26.7%和80.5%，且MAGE-A10基因的表达与患者短生存期密切相关。另一研究[44]发现：在晚期GC和胃食管交界处癌治愈性胃切除术后，发生GC肝转移的患者体内MAGE-A10的表达水平明显上调，MAGE-A10染色对发生GC肝转移的敏感性和特异性分别为58.3%和84.5%。上述研究表明MAGE-A10有望成为GC和GC肝转移预测的标志物。

2.7. MAGE-A12

MAGE-A12在GC、乳腺癌、肝细胞癌、人皮肤鳞状细胞癌等多种肿瘤中均有表达，其高表达可显著增强肿瘤细胞的迁移和侵袭能力并与患者较差的预后明显相关[45-48]。国外研究[45]表明乳腺癌细胞的侵袭性可能与MAGE-A12受FOXA1转录因子的调控有关，MAGE-A12及其基因组蛋白质标志物是继乳腺癌个体表达的激素受体和人表皮生长因子受体2(human epldermal growth factor receptor-2，HER2)之后进行分子亚型分类的新成员，具有对乳腺癌细胞进行分类的潜力。Zhao等[47]发现MAGE-A12可能通过介导p21基因下调参与人皮肤鳞状细胞癌的发生，同时也表明MAGE-A12可作为人皮肤鳞状细胞癌的分子生物标志物。在GC的研究中，MAGE-A12表现出很好的靶向性，Wu等[48]研究发现MAGE-A12只在一小部分GC组织中异常表达，且MAGE-A12的过表达状态在晚期GC中更常见，用免疫组织化学数据进行生存分析发现MAGE-A12的高表达与不良预后呈正相关。以上研究均说明MAGE-A12在成为肿瘤分子标志物方面有较好的研究前景。

3. MAGE-A家族与GC的临床转化和治疗

基于MAGE-A家族的高度组织特异性，已经针对部分家族成员开展了肿瘤疫苗研究。肿瘤疫苗是通过将特异性的肿瘤抗原以肿瘤细胞、肿瘤相关蛋白或多肽等形式注入患者体内，克服肿瘤引起的机体免疫抑制状态，增强免疫原性，激活患者自身的免疫系统，诱导机体细胞和体液免疫应答，从而达到控制或清除肿瘤的目的[5]。截至目前，MAGE-A家族成员在多种实体肿瘤如黑色素瘤、非小细胞肺癌、膀胱尿路上皮癌、头颈癌等中的临床转化研究均在探索。在GC的免疫治疗中，可以检测到针对MAGE-A的细胞和体液免疫应答，进一步证明MAGE-A有抗肿瘤作用。

目前针对MAGE-A3的GC疫苗相关实验陆续开展，已有动物实验证明接种MAGE-A3疫苗，可在小鼠体内诱导产生细胞免疫反应，如Yang等[7]通过将含有MAGE-A3衍生的CD4+-CD8+ T细胞表位肽的纳米疫苗注射到移植GC的小鼠体内，诱导产生靶向MAGE-A3的CTL来杀伤GC细胞，实验组肿瘤的消退率为37.81%。Lin等[49]将含MAGE-A3基因的慢病毒载体导入人的脐带血来诱导DC高表达CD80、CD86和HLA-DR，从而激活CTL杀伤肿瘤细胞。目前关于MAGE-A3的T细胞疫苗与腺病毒疫苗的临床试验逐步开展，如一项能够识别MAGE-A3的基因工程改造T细胞在成人晚期实体瘤中的安全性和有效性的I期临床试验(NCT03139370)正在进行(表1)。

表1.

MAGE-A3、MAGE-A4、MAGE-A6在胃癌中的临床试验

Table 1 Clinical trials of MAGE-A3, MAGE-A4, and MAGE-A6 in gastric cancer

No. Clinical staging Research title Intervention Disease Project location Project status Registration number
1 I ADP-A2M4CD8 in MAGE-A4-positive tumors in HLA-A2+ subjects Autologous transgenic ADP-A2M4CD8 cells Gastric cancer USA Recruiting NCT04044859
2 I MAGE-A4ᶜ¹º³² T in MAGE-A4-positive tumors in HLA-A2+ subjects Autologous transgenic MAGE-A4ᶜ¹º³² T cells or autologous transgenic MAGE-A4ᶜ¹º³² T cells combined with low-dose radiation Gastric cancer USA Recruiting NCT03132922
3 I Phase 1 Study of MAGE-A4 TCR gene modified T cells for the treatment of malignant tumors MAGE-A4 TCR gene modification in T cells Solid cancer CHN Unknown NCT01694472
4 I Safety and efficacy of KITE-718 in HLA-DPB1*04꞉01 adult advanced cancer MAGE-A3/A6 T cell receptor engineered T cells (KITE-718); cyclophosphamide; fludarabine Solid cancer USA Recruiting NCT03139370
5 I/II MG1MA3 or combination with adenovirus/MAGE-A3 vaccine in incurable MAGE-A3-positive solid tumors MG1 Maraba/MAGE-A3 (MG1MA3) virus alone or adenovirus/MAGE-A3 (AdMA3) combination Solid tumor CAN Stop recruiting NCT02285816
6 II Study of ADP-A2M4CD8 in HLA-A2+ subjects with MAGE-A4 positive esophageal cancer or gastroesophageal junction cancer (SURPASS-2) Autologous transgenic ADP-A2M4CD8 cells Gastroesophageal junction cancer Not available Recruitment has not begun NCT04752358
7 I Phase I Study of TBI-1201 MAGE-A4-specific TCR gene-transduced T lymphocytes (TBI-1201); cyclophosphamide; fludarabine Solid cancer JP Launching NCT02096614
8 I/II Safety and efficacy of IMC-C103C or combination therapy with atezolizumab in MAGE-A4 positive tumors in HLA-A2+ subjects IMC-C103C; atezumab Solid cancer USA Recruiting NCT03973333
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目前各国陆续开展针对MAGE-A4的GC疫苗的临床实验(表1)。一项对20例晚期食管癌、GC、肺癌患者皮下注射含300 μg MAGE-A4蛋白的CHP-MAGE-A4疫苗(共6剂)的临床试验[50]结果显示：4例高表达MAGE-A4和MHC-I类抗原的患者发生了MAGE-A4特异性体液免疫应答，且这4名患者比未引起体液免疫反应的患者总存活率更高。3例患者发生了CD4+ T细胞反应，6例发生了CD8+ T细胞反应，且诱导产生MAGE-A4特异性干扰素的CD8+ T细胞患者比未诱导CD8+ T细胞的患者存活时间更长。该研究提示CHP-MAGE-A4疫苗是安全的，且MAGE-A4可诱导特异性免疫细胞杀伤肿瘤细胞。

此外，对于MAGE-A家族的其他成员(MAGE-A6、MAGE-A10、MAGE-A12)的免疫实验也均有进展。Vujanovic等[51]研究发现MPHF2肽引发的CD4+ T细胞对MAGE-A6(172-187)肽的功能亲和力大约是用MAGE-A6肽引发的CD4+ T细胞的1 000倍，MAGE-A6/MPHF2 Th表位在临床上可用于治疗和/或监测高表达MAGE-A6的癌症患者。MAGE-A10疫苗接种实验[52]发现只有能够高效识别抗原肽的CD8+ T细胞才能够裂解表达MAGE-A10的肿瘤细胞。Akiyama等[53]鉴定出针对MAGE-A12的新型CTL表位为IFSKASEYL肽，该表位可能是基于肽的癌症疫苗的良好候选者。

4. 展 望

MAGE-A家族中MAGE-A1、MAGE-A2、MAGE- A3、MAGE-A4、MAGE-A6、MAGE-A10、MAGE-A12与GC的发生、发展、转移及预后密切相关，但其确切的作用机制仍需进一步探究。目前，在GC中MAGE-A家族成员开展临床试验的仅有MAGE-A3、MAGE-A4、MAGE-A6，而以其他家族成员为靶点的临床试验研究还未开展。基于MAGE-A家族的免疫治疗部分有效，未来还需纳入更大的样本量来开展II期/III期临床试验，进一步评估其安全性和有效性。由于GC组织具有高度的异质性，因此基于MAGE-A家族的个体化免疫治疗是今后的研究重点，其能否作为肿瘤分子标志物也有待继续研究。

基金资助

兰州大学第二医院“萃英学子科研培育”计划。

This work was supported by the Cuiying Scientific Training Program for Undergraduates of Lanzhou University Second Hospital, China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

贾祺 文献检索，论文撰写及修改；咸小红、李泱润、慕嘉欣 文献检索，论文撰写；杜志兴 论文审阅及修改。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202302260.pdf

参考文献

  • 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA A Cancer J Clin, 2015, 65(1): 5-29. 10.3322/caac.21254. [DOI] [PubMed] [Google Scholar]
  • 2. 陈博晋, 胡星怡, 赵菁文, 等. 免疫治疗在胃癌新辅助治疗中的研究进展[J]. 肿瘤防治研究, 2022, 49(7): 727-732. 10.3971/j.issn.1000-8578.2022.21.1241. [DOI] [Google Scholar]; CHEN Bojin, HU Xingyi, ZHAO Jingwen, et al. Current status of immunotherapy in neoadjuvant therapy for gastric cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(7): 727-732. 10.3971/j.issn.1000-8578.2022.21.1241. [DOI] [Google Scholar]
  • 3. 陈卫昌, 石通国, 朱婧菡, 等. 胃肠肿瘤免疫治疗进展[J]. 肿瘤防治研究, 2022, 49(7): 639-643. 10.3971/j.issn.1000-8578.2022.21.1527. [DOI] [Google Scholar]; CHEN Weichang, SHI Tongguo, ZHU Jinghan, et al. Progress on immunotherapy of gastrointestinal cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(7): 639-643. 10.3971/j.issn.1000-8578.2022.21.1527. [DOI] [Google Scholar]
  • 4. 朱军, 黄美金, 陈宏. 进展期胃癌免疫治疗的研究进展[J]. 癌症进展, 2022, 20(12): 1189-1193. 10.11877/j.issn.1672-1535.2022.20.12.01. [DOI] [Google Scholar]; ZHU Jun, HUANG Meijin, CHEN Hong. Research progress of immunotherapy for advanced gastric cancer[J]. Oncology Progress, 2022, 20(12): 1189-1193. 10.11877/j.issn.1672-1535.2022.20.12.01. [DOI] [Google Scholar]
  • 5. 焦宗林, 刘琳, 都兴隆, 等. 癌/睾丸抗原在肺癌中的研究进展[J]. 现代肿瘤医学, 2019, 27(13): 2398-2402. 10.3969/j.issn.1672-4992.2019.13.039. 30805772 [DOI] [Google Scholar]; JIAO Zonglin, LIU Lin, DU Xinglong, et al. Research progress of cancer/testis antigen in lung cancer[J]. Journal of Modern Oncology, 2019, 27(13): 2398-2402. 10.3969/j.issn.1672-4992.2019.13.039. [DOI] [Google Scholar]
  • 6. Esfandiary A, Ghafouri-Fard S. MAGE-A3: an immunogenic target used in clinical practice[J]. Immunotherapy, 2015, 7(6): 683-704. 10.2217/imt.15.29. [DOI] [PubMed] [Google Scholar]
  • 7. Yang J, Li ZH, Zhou JJ, et al. Preparation and antitumor effects of nanovaccines with MAGE-3 peptides in transplanted gastric cancer in mice[J]. Chin J Cancer, 2010, 29(4): 359-364. 10.5732/cjc.009.10541. [DOI] [PubMed] [Google Scholar]
  • 8. van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma[J]. Science, 1991, 254(5038): 1643-1647. 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]
  • 9. Inoue H, Li J, Honda M, et al. MAGE-1 mRNA expression in gastric carcinoma[J]. Int J Cancer, 1995, 64(1): 76-77. 10.1002/ijc.2910640115. [DOI] [PubMed] [Google Scholar]
  • 10. Ishihara M, Kageyama S, Miyahara Y, et al. MAGE-A4, NY-ESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours[J]. BMC Cancer, 2020, 20(1): 606. 10.1186/s12885-020-07098-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Kuldkepp A, Karakai M, Toomsoo E, et al. Cancer-testis antigens MAGEA proteins are incorporated into extracellular vesicles released by cells[J]. Oncotarget, 2019, 10(38): 3694-3708. 10.18632/oncotarget.26979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. 蔡一奇, 程开, 陈旭东, 等. MAGE-A3多克隆抗体的制备及在胃癌细胞检测中的应用[J]. 温州医科大学学报, 2017, 47(5): 318-324. 10.3969/j.issn.2095-9400.2017.05.002. [DOI] [Google Scholar]; CAI Yiqi, CHENG Kai, CHEN Xudong, et al. Preparation of MAGE-A3 polyclonal antibody and its application in detection of human gastric cancer cell[J]. Journal of Wenzhou Medical University, 2017, 47(5): 318-324. 10.3969/j.issn.2095-9400.2017.05.002. [DOI] [Google Scholar]
  • 13. 李英彬, 王万祥, 苏秀兰. MAGEA1和MAGEA3基因在胃癌中的表达及应用[J]. 内蒙古医学杂志, 2008, 40(2): 204-206. 10.3969/j.issn.1004-0951.2008.02.032. [DOI] [Google Scholar]; LI Yingbin, WANG Wanxiang, SU Xiulan. The expression and application of MAGEA1 and MAGEA3 genes in human gastric carcinoma[J]. Inner Mongolia Medical Journal, 2008, 40(2): 204-206. 10.3969/j.issn.1004-0951.2008.02.032. [DOI] [Google Scholar]
  • 14. Meng XY, Sun XQ, Liu ZL, et al. A novel era of cancer/testis antigen in cancer immunotherapy[J]. Int Immunopharmacol, 2021, 98: 107889. 10.1016/j.intimp.2021.107889. [DOI] [PubMed] [Google Scholar]
  • 15. Ogata K, Aihara R, Mochiki E, et al. Clinical significance of melanoma antigen-encoding gene-1 (MAGE-1) expression and its correlation with poor prognosis in differentiated advanced gastric cancer[J]. Ann Surg Oncol, 2011, 18(4): 1195-1203. 10.1245/s10434-010-1399-z. [DOI] [PubMed] [Google Scholar]
  • 16. 吴晓江, 王飲, 季加孚. 胃癌中肿瘤/睾丸抗原表达研究及NY-ESO-1 蛋白的自身抗体检测[J]. 北京大学学报(医学版), 2005, 37(3): 252-256. [PubMed] [Google Scholar]; WU Xiaojiang, WANG Yu, JI Jiafu. Analysis of CT antigen expression and humoral immunogenicity of NY-ESO-1 protein in gastric carcinoma[J]. Journal of Peking University. Health Sciences, 2005, 37(3): 252-256. [PubMed] [Google Scholar]
  • 17. Futawatari N, Fukuyama T, Yamamura R, et al. Early gastric cancer frequently has high expression of KK-LC-1, a cancer-testis antigen[J]. World J Gastroenterol, 2017, 23(46): 8200-8206. 10.3748/wjg.v23.i46.8200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Gibbs P, Hutchins AM, Dorian KT, et al. MAGE-12 and MAGE-6 are frequently expressed in malignant melanoma[J]. Melanoma Res, 2000, 10(3): 259-264. [PubMed] [Google Scholar]
  • 19. Suzuki S, Sasajima K, Sato Y, et al. MAGE-a protein and MAGE-A10 gene expressions in liver metastasis in patients with stomach cancer[J]. Br J Cancer, 2008, 99(2): 350-356. 10.1038/sj.bjc.6604476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. de Smet C, Lurquin C, van der Bruggen P, et al. Sequence and expression pattern of the human MAGE2 gene[J]. Immunogenetics, 1994, 39(2): 121-129. 10.1007/BF00188615. [DOI] [PubMed] [Google Scholar]
  • 21. Honda T, Tamura G, Waki T, et al. Demethylation of MAGE promoters during gastric cancer progression[J]. Br J Cancer, 2004, 90(4): 838-843. 10.1038/sj.bjc.6601600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. He SB, Wang L, Wu YG, et al. CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo[J]. J Exp Clin Cancer Res, 2010, 29(1): 37. 10.1186/1756-9966-29-37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Park S, Han JE, Kim HG, et al. Inhibition of MAGEA2 regulates pluripotency, proliferation, apoptosis, and differentiation in mouse embryonic stem cells[J]. J Cell Biochem, 2020, 121(11): 4667-4679. 10.1002/jcb.29692. [DOI] [PubMed] [Google Scholar]
  • 24. Gjerstorff MF, Harkness L, Kassem M, et al. Distinct GAGE and MAGE-A expression during early human development indicate specific roles in lineage differentiation[J]. Hum Reprod, 2008, 23(10): 2194-2201. 10.1093/humrep/den262. [DOI] [PubMed] [Google Scholar]
  • 25. Park S, Sung Y, Jeong J, et al. Critical roles of hMAGEA2 in induced pluripotent stem cell pluripotency, proliferation, and differentiation[J]. Cell Biochem Funct, 2017, 35(7): 392-400. 10.1002/cbf.3286. [DOI] [PubMed] [Google Scholar]
  • 26. Jung EJ, Kim MA, Lee HS, et al. Expression of family A melanoma antigen in human gastric carcinoma[J]. Anticancer Res, 2005, 25(3B): 2105-2111. [PubMed] [Google Scholar]
  • 27. Pan YB, Liu GH, Zhou FL, et al. DNA methylation profiles in cancer diagnosis and therapeutics[J]. Clin Exp Med, 2018, 18(1): 1-14. 10.1007/s10238-017-0467-0. [DOI] [PubMed] [Google Scholar]
  • 28. Salmaninejad A, Zamani MR, Pourvahedi M, et al. Cancer/testis antigens: expression, regulation, tumor invasion, and use in immunotherapy of cancers[J]. Immunol Invest, 2016, 45(7): 619-640. 10.1080/08820139.2016.1197241. [DOI] [PubMed] [Google Scholar]
  • 29. Manici S, Sturniolo T, Imro MA, et al. Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11[J]. J Exp Med, 1999, 189(5): 871-876. 10.1084/jem.189.5.871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Imai Y, Shichijo S, Yamada A, et al. Sequence analysis of the MAGE gene family encoding human tumor-rejection antigens[J]. Gene, 1995, 160(2): 287-290. 10.1016/0378-1119(94)00680-q. [DOI] [PubMed] [Google Scholar]
  • 31. 高建全, 张宇祥, 呼玲玲, 等. MAGEA4在非小细胞肺癌中的表达以及与患者预后的关系[J]. 临床肺科杂志, 2020, 25(6): 895-901. 10.3969/j.issn.1009-6663.2020.06.021. [DOI] [Google Scholar]; GAO Jianquan, ZHANG Yuxiang, HU Lingling, et al. MAGEA4 expression in NSCLC cancer and its correlation with patient’s prognosis[J]. Journal of Clinical Pulmonary Medicine, 2020, 25(6): 895-901. 10.3969/j.issn.1009-6663.2020.06.021. [DOI] [Google Scholar]
  • 32. Werner S, Chen HD, Butt J, et al. Evaluation of the diagnostic value of 64 simultaneously measured autoantibodies for early detection of gastric cancer[J]. Sci Rep, 2016, 6: 25467. 10.1038/srep25467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Kwon S, Kang SH, Ro J, et al. The melanoma antigen gene as a surveillance marker for the detection of circulating tumor cells in patients with breast carcinoma[J]. Cancer, 2005, 104(2): 251-256. 10.1002/cncr.21162. [DOI] [PubMed] [Google Scholar]
  • 34. Hartmann S, Meyer TJ, Brands RC, et al. MAGE-A expression clusters and antineoplastic treatment in head and neck cancer[J]. Int J Mol Med, 2015, 35(6): 1675-1682. 10.3892/ijmm.2015.2174. [DOI] [PubMed] [Google Scholar]
  • 35. Wu F, Liu F, Dong LM, et al. MiR-1273g silences MAGEA3/6 to inhibit human colorectal cancer cell growth via activation of AMPK signaling[J]. Cancer Lett, 2018, 435: 1-9. 10.1016/j.canlet.2018.07.031. [DOI] [PubMed] [Google Scholar]
  • 36. Pineda CT, Ramanathan S, Fon Tacer K, et al. Degradation of AMPK by a cancer-specific ubiquitin ligase[J]. Cell, 2015, 160(4): 715-728. 10.1016/j.cell.2015.01.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Pan SJ, Ren J, Jiang H, et al. MAGEA6 promotes human glioma cell survival via targeting AMPKα1[J]. Cancer Lett, 2018, 412: 21-29. 10.1016/j.canlet.2017.09.051. [DOI] [PubMed] [Google Scholar]
  • 38. Ye XT, Xie J, Huang H, et al. Knockdown of MAGEA6 activates AMP-activated protein kinase (AMPK) signaling to inhibit human renal cell carcinoma cells[J]. Cell Physiol Biochem, 2018, 45(3): 1205-1218. 10.1159/000487452. [DOI] [PubMed] [Google Scholar]
  • 39. Tsang YH, Wang YM, Kong K, et al. Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression[J/OL]. eLife, 2020, 9: e48963 [2021-12-30]. 10.7554/eLife.48963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. van Tongelen A, Loriot A, de Smet C. Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes[J]. Cancer Lett, 2017, 396: 130-137. 10.1016/j.canlet.2017.03.029. [DOI] [PubMed] [Google Scholar]
  • 41. Filho PA, López-Albaitero A, Xi LQ, et al. Quantitative expression and immunogenicity of MAGE-3 and-6 in upper aerodigestive tract cancer[J]. Int J Cancer, 2009, 125(8): 1912-1920. 10.1002/ijc.24590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Endo M, Kanda M, Sawaki K, et al. Tissue expression of melanoma-associated antigen A6 and clinical characteristics of gastric cancer[J]. Anticancer Res, 2019, 39(11): 5903-5910. 10.21873/anticanres.13794. [DOI] [PubMed] [Google Scholar]
  • 43. Schultz-Thater E, Piscuoglio S, Iezzi G, et al. MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies[J]. Int J Cancer, 2011, 129(5): 1137-1148. 10.1002/ijc.25777. [DOI] [PubMed] [Google Scholar]
  • 44. Fujiya K, Terashima M, Ohshima K, et al. MAGEA10 expression is a predictive marker of early hepatic recurrence after curative gastrectomy for gastric and gastroesophageal junction cancer[J]. Gastric Cancer, 2021, 24(2): 341-351. 10.1007/s10120-020-01123-y. [DOI] [PubMed] [Google Scholar]
  • 45. Oh C, Kim HR, Oh S, et al. Epigenetic upregulation of MAGE-a isoforms promotes breast cancer cell aggressiveness[J]. Cancers (Basel), 2021, 13(13): 3176. 10.3390/cancers13133176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Li R, Gong J, Xiao CC, et al. A comprehensive analysis of the MAGE family as prognostic and diagnostic markers for hepatocellular carcinoma[J]. Genomics, 2020, 112(6): 5101-5114. 10.1016/j.ygeno.2020.09.026. [DOI] [PubMed] [Google Scholar]
  • 47. Zhao GH, Bae JY, Zheng ZL, et al. Overexpression and implications of melanoma-associated antigen A12 in pathogenesis of human cutaneous squamous cell carcinoma[J]. Anticancer Res, 2019, 39(4): 1849-1857. 10.21873/anticanres.13292. [DOI] [PubMed] [Google Scholar]
  • 48. Wu J, Wang J, Shen W. Identification of MAGEA12 as a prognostic outlier gene in gastric cancers[J]. Neoplasma, 2017, 64(2): 238-243. 10.4149/neo_2017_210. [DOI] [PubMed] [Google Scholar]
  • 49. Lin LY, Wei JB, Chen YQ, et al. Induction of antigen-specific immune responses by dendritic cells transduced with a recombinant lentiviral vector encoding MAGE-A3 gene[J]. J Cancer Res Clin Oncol, 2014, 140(2): 281-289. 10.1007/s00432-013-1552-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Saito T, Wada H, Yamasaki M, et al. High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine[J]. Vaccine, 2014, 32(45): 5901-5907. 10.1016/j.vaccine.2014.09.002. [DOI] [PubMed] [Google Scholar]
  • 51. Vujanovic L, Mandic M, Olson WC, et al. A mycoplasma peptide elicits heteroclitic CD4+ T cell responses against tumor antigen MAGE-A6[J]. Clin Cancer Res, 2007, 13(22 Pt 1): 6796-6806. 10.1158/1078-0432.CCR-07-1909. [DOI] [PubMed] [Google Scholar]
  • 52. Dutoit V, Rubio-Godoy V, Dietrich PY, et al. Heterogeneous T-cell response to MAGE-A10(254-262): high avidity-specific cytolytic T lymphocytes show superior antitumor activity[J]. Cancer Res, 2001, 61(15): 5850-5856. [PubMed] [Google Scholar]
  • 53. Akiyama Y, Komiyama M, Nakamura Y, et al. Identification of novel MAGE-A6- and MAGE-A12-derived HLA-A24-restricted cytotoxic T lymphocyte epitopes using an in silico peptide-docking assay[J]. Cancer Immunol Immunother, 2012, 61(12): 2311-2319. 10.1007/s00262-012-1298-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

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