修回日期: 2013-09-24
接受日期: 2013-09-30
在线出版日期: 2013-11-08
细胞毒素相关基因A蛋白(cytotoxin-associated gene A, CagA)是幽门螺杆菌重要毒力因子之一, 亦被称为细菌癌蛋白, 可通过Ⅳ型分泌系统易位进入胃上皮细胞, 干扰多条信号转导通路. 细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)通路在细胞信号传导中处于枢纽地位, 癌蛋白CagA可通过激活ERK信号通路对细胞的增殖、凋亡、分散和转移等生物学行为产生影响, 与胃癌的发生、发展有关. 本文对CagA、ERK信号通路与胃癌的研究进展做一综述.
核心提示: 癌蛋白细胞毒素相关基因A蛋白(cytotoxin-associated gene A, CagA)通过激活细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)信号通路导致宿主细胞发生恶性转化, 在胃癌的发生、发展过程中可能发挥重要作用. 研究CagA、ERK信号通路与胃癌的关系, 将为揭示CagA蛋白的致癌机制提供新的研究证据, 并有望为幽门螺杆菌诱发胃癌的分子机制研究提供新思路和新靶点.
引文著录: 邢军明, 黄志刚. 癌蛋白CagA、ERK信号通路与胃癌关系的研究进展. 世界华人消化杂志 2013; 21(31): 3363-3368
Revised: September 24, 2013
Accepted: September 30, 2013
Published online: November 8, 2013
Cytotoxin-associated gene A (CagA) of Helicobacter pylori is the first identified bacterial oncoprotein that plays a critical role in gastric carcinogenesis. Upon delivery into gastric epithelial cells via type IV secretion, CagA can interfere with a number of host signaling pathways. Extracellular signal-regulated kinase (ERK) signaling pathway is a hub in cellular signal transduction, through which CagA elicits a series of cellular events including cell proliferation, apoptosis, scatter and metastasis, all of which are associated with gastric carcinogenesis. Here we perform a review of the association between CagA/ERK signaling pathway and gastric cancer.
- Citation: Xing JM, Huang ZG. Association between CagA/ERK signaling pathway and gastric cancer. Shijie Huaren Xiaohua Zazhi 2013; 21(31): 3363-3368
- URL: https://www.wjgnet.com/1009-3079/full/v21/i31/3363.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i31.3363
胃癌是临床上常见的恶性肿瘤之一, 在全球肿瘤死因谱中稳居第2位. 尽管早已明确, 幽门螺杆菌(Helicobacter pylori, H. pylori)是人类胃癌的Ⅰ类(即肯定的)致癌原, 但迄今为止, H. pylori诱发胃癌的分子机制尚未阐明[1-3]. 细胞毒素相关基因A蛋白(cytotoxin-associated gene A, CagA)是H. pylori感染导致宿主产生炎性反应及癌变的重要效应蛋白, 亦被称为细菌癌蛋白. CagA蛋白在宿主细胞内通过干扰多条信号途径, 对细胞的增殖、凋亡、分化等功能产生影响, 其中细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)通路是涉及CagA蛋白致病机制的关键信号通路之一[4-6]. 本文对于H. pylori癌蛋白CagA、ERK信号通路与胃癌的研究进展做一综述.
H. pylori是一种可长期定植于人类胃黏膜的革兰氏阴性螺旋形微需氧菌, 在全世界范围内感染率超过50%. 来自世界各地的流行病学研究证实, 幽门螺杆菌感染是诱发胃癌的重要危险因素[7-9]. CagA蛋白是H. pylori最重要的毒力因子之一, 通常根据CagA蛋白表达与否将H. pylori分为两型: Ⅰ型为高毒力株, 含cagA基因, 表达CagA和VacA蛋白, 具有空泡毒素活性; Ⅱ型为低毒力株, 不含cagA基因, 不表达CagA和VacA蛋白, 无空泡毒素活性[10]. 研究显示, 感染高毒力株患者较之感染低毒力株者, 发生萎缩性胃炎和胃腺癌的危险性明显升高, 提示CagA可能与H. pylori相关胃癌的发生有关[11-14].
1993年Tunmmuru等[15]首次用酶切H. pylori全基因组的方法克隆到了cagA基因, 其开放阅读框为4821 bp, 编码1181个氨基酸, 并发现所有15株产VacA菌株均含有该基因, 命名为细胞毒素相关基因A, 相应蛋白则命名为CagA. cagA基因位于cag致病岛(cag pathogenity island, cagPAI)一侧末端, cagPAI长约40 kb, 定位于谷氨酸消旋酶基因内部, 其G+C含量(35%)与基因组中的其他部分(39%)不同, 提示该基因群可能是在进化过程中由其他生物体通过水平转移而来[16,17]. cagPAI内含有编码cagA和Ⅳ型分泌系统等31个基因. Ⅳ型分泌系统充当分子注射器样作用, 可以将CagA蛋白"注入"宿主细胞, CagA是第一个通过此方式进入真核细胞发挥作用的细菌蛋白[18,19].
CagA蛋白易位进入宿主细胞后, 定位于宿主细胞质膜的内表面, 并在此经Src家族蛋白激酶(Src family kinases, SFKs)作用发生酪氨酸磷酸化, 磷酸化位点位于CagA分子C端谷氨酸-脯氨酸-异亮氨酸-酪氨酸-丙氨酸(EPIYA)重复序列中的酪氨酸残基[20,21]. 一般根据EPIYA重复序列可将CagA分为东亚型(含EPIYA-A、EPIYA-B和EPIYA-D重复基序, 简称A-B-D型)和西方型(含EPIYA-A、EPIYA-B和1个或多个EPIYA-C重复基序, 简称A-B-C型)[22]. CagA的东亚型与西方型相比具有较强的诱导细胞发生蜂鸟样改变的能力. 感染含东亚型CagA的H. pylori患者其胃黏膜炎症程度及胃炎、萎缩性胃炎的严重程度均高于感染含西方型CagA的H. pylori患者, 提示感染含东亚型CagA的H. pylori菌株致胃癌的危险性更高[23-25].
ERK是80年代末期发现的一类丝氨酸/苏氨酸激酶, 是传递丝裂原信号的信号蛋白. 经典的ERK通路的信号传递过程包括: 细胞外信号→细胞受体→细胞内酪氨酸激酶→Ras蛋白→Raf蛋白→细胞外信号调节激酶激酶(extracellular-signal regulated kinase kinase, MEKK)→MEK→ERK1/2→转录因子→相关基因表达→细胞增生、转化[26-28]. 其中Ras蛋白是一种类似鼠肉瘤病毒的细胞癌蛋白, 具有活化态的GTP结合构象与失活态的GDP结合构象. 两种构象可以相互转变, 在信号转导过程中发挥开关作用. Ras蛋白激活将Raf蛋白从胞浆转移到胞膜, 在胞膜上Raf蛋白被激活[29,30]. Raf蛋白是丝裂原活化蛋白激酶的一种激酶, Raf蛋白被激活后, 其C端催化区能与MEK结合, 并使其催化区第Ⅷ亚区中两个丝氨酸磷酸化, 从而使MEK激活. MEK丝裂原介导的细胞外激酶属于少有的双重特异性激酶, 使酪氨酸和苏氨酸两个调节位点磷酸化而激活ERK[31,32]. 激活的ERK1/2转移到胞核, 通过磷酸化转录因子、细胞骨架相关蛋白、酶类等多种底物来调节相关基因表达, 进而参与细胞生长、发育、分裂、迁移及凋亡等多种生理过程[33-36].
CagA可通过依赖和不依赖于酪氨酸磷酸化的方式激活ERK通路: 首先, 酪氨酸磷酸化的CagA可激活含SH-2结构域的酪氨酸磷酸酶(tyrosine phosphatase, SHP-2), SHP-2由3个部分组成: N端区域有两个串联重复的SH-2结构域(N-SH2和C-SH2); 一个单一的催化蛋白酪氨酸磷酸酶(protein tyrosine phosphatase, PTP)结构域和碳端部分[37-39]. SH-2结构域在蛋白质组成中专一地同含有磷酸化酪氨酸的肽类相互作用. 由SHP-2的SH-2结构域识别的肽类同源序列, 能很好地与CagA的EPIYA基序的侧翼序列吻合. SHP-2是细胞多条信息传递和细胞骨架重构中的重要蛋白, 可通过一系列被激活的受体酪氨酸激酶, 调控细胞内的信号转导事件[40-42]. 磷酸化的CagA特异性结合SHP-2的SH-2结构域使SHP-2活化, 致使Ras/Raf/MEK/ERK通路依次激活, 导致细胞骨架重排和细胞拉伸即"蜂鸟样表型", 这是CagA蛋白导致细胞表型发生改变的主要机制之一[43,44].
其次, CagA在体内、体外均可直接与生长因子受体结合蛋白-2(growth factor receptor-bound protein 2, GRB-2)相互作用, 发挥生长因子样作用, 激活RAS/MEK/ERK信号通路, 导致细胞增殖和胞间解离, 而这一作用与CagA酪氨酸磷酸化无关[45]. 另外, CagA还可经由RAS/RAF/MEK/ERK信号通路可直接激活核因子-κB(nuclear factor κB, NF-κB), 诱导慢性炎症相关因子白介素-8(interleukin-8, IL-8)的释放, 同样该作用也与CagA酪氨酸磷酸化无关[46].
胃泌素(gastrin)是一种重要的胃肠激素, 胃泌素的表达水平随着肿瘤分化程度的降低而显著升高, 与刺激肿瘤细胞生长及肿瘤的淋巴结转移有关[47-49]. Takaishi等[50]研究认为, 在H. pylori感染相关性胃癌的发生、发展过程中, 胃泌素是其辅助因子. 新近Zhou等[51]发现, CagA可通过MEK/ERK和JAK2通路上调胃泌素基因的表达, 该研究为CagA激活ERK通路促进胃癌的发生提供了证据.
CagA蛋白可增加正常胃黏膜细胞对致癌物二甲基肼的敏感性, 促进正常细胞发生恶性转化. ERK1/2通路特异性抑制剂PD98059可使cagA转染的细胞DNA合成显著受抑制, 细胞增殖活性明显下降, 并且转染cagA的细胞ERK1/2活性、RAS/MAPK通路的IQGAP-2蛋白(IQ domain GTPase-activating proteins, IQGAP-2)、R-Ras和B-Raf表达水平显著高于致癌物二甲基肼处理组和对照组, 提示CagA蛋白可通过激活ERK1/2通路诱导胃黏膜上皮细胞发生转化[52].
Meyer-ter-Vehn等[53]研究报道, 胃上皮细胞在H. pylori(CagA+)作用下可激活转录因子激活蛋白1(activator protein-1, AP-1), 从而诱导原癌基因c-fos、c-jun的表达, 其作用机制与ERK/MAPK级联激活, 导致转录因子Ets样蛋白1(Ets-like protein 1, Elk-1)磷酸化及促进原癌基因c-fos的转录有关, 而H. pylori(CagA-)菌株与胃上皮细胞共培养, 并不会产生此效应, 提示CagA激活ERK通路与原癌基因的表达有关. Xu等[54]研究发现, H. pylori菌株(CagA+)感染以及异位表达CagA蛋白均可使鸟氨酸脱羧酶(ornithine decarboxylase, ODC)表达上调, ODC是催化多胺形成的关键酶, 而多胺是促进细胞生长的关键成分. 采用信号通路抑制剂处理细胞后发现, CagA蛋白通过激活Src/MEK/ERK/c-Myc通路, 上调ODC表达, 发挥其促进细胞增殖作用.
蛋白磷酸酶2A癌性抑制因子(cancerous inhibitor of protein phosphatase 2A, CIP2A)是新近发现的人类致癌蛋白, 在胃癌组织呈高表达[55]. Zhao等[56]报道, CIP2A表达上调与CagA蛋白及CagA的磷酸化作用有关, 并且该作用是通过激活Src/Ras/MAPK/ERK通路实现的. Liu等[57]选择永生化胃黏膜上皮细胞GES-1, 研究CagA蛋白对抑癌基因Runx3的影响, 结果发现CagA通过Src/MEK/ERK和p38 MAPK通路对抑癌基因Runx3发挥抑制作用. 综上可知, CagA蛋白可通过ERK信号通路调控生长因子、激活癌基因、抑制抑癌基因表达, 导致细胞的增殖、凋亡异常, 进而在胃癌的发生、发展过程中发挥重要作用.
此外, CagA激活ERK信号导致细胞癌变还与细胞极性有关. 在非极性上皮细胞中, CagA异常活化ERK信号通路可诱导细胞周期蛋白依赖性激酶抑制因子p21WAF1/CIP1累积, 从而导致细胞衰老样增殖阻滞; 而在极性上皮细胞中, CagA激活ERK信号可通过活化鸟嘌呤核苷酸交换因子H1-RhoA-RhoA相关激酶C-Myc信号途径抑制p21WAF1/CIP1表达, 诱导细胞增殖. 以上研究提示, CagA可利用细胞极性-ERK信号通路来诱发癌变[58]. 新近CagA激活ERK诱发癌变也获得了人群遗传易感性方面的研究证据[59]: 针对CagA激活ERK信号通路下游涉及的8个基因24个SNPs进行研究发现, ERK rs5999749、Dock180 rs4635002和C3G rs7853122等3个位点的遗传变异与胃癌有关, 首次证实了CagA激活ERK通路会增加癌症的风险, 该研究进一步丰富了与CagA、ERK信号通路有关的胃癌的病因学研究内容.
ERK信号通路是涉及H. pylori癌蛋白CagA致癌机制的关键信号通路之一, ERK通路的异常激活在胃癌细胞的表型恶化、细胞增殖、凋亡等过程中发挥重要作用. 今后要针对CagA蛋白激活ERK信号通路后的下游分子事件、对细胞恶性生物学行为的影响、对表观遗传学标志物的作用以及ERK通路与其他信号通路的相互作用关系等进一步展开研究, 以期为揭示CagA蛋白的致癌机制提供新的研究证据, 并有望为H. pylori诱发胃癌的分子机制研究提供新的思路和新靶点.
胃癌在全球肿瘤死因谱中稳居第二位, 目前虽已明确幽门螺杆菌(Helicobacter pylori, H. pylori)感染是导致胃癌的重要危险因素, 但其诱发胃癌的分子机制尚不清楚. 细胞毒素相关基因A蛋白(cytotoxin-associated gene A, CagA)是H. pylori感染导致宿主产生炎性反应的重要效应蛋白, CagA在宿主细胞内可干扰多条信号途径, 而细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)通路在细胞信号传导中处于枢纽地位. CagA蛋白可通过激活ERK信号通路对细胞的增殖、凋亡、分散和转移等生物学行为产生影响. 研究CagA蛋白、ERK信号通路与胃癌的关系, 对于揭示H. pylori相关胃癌的分子机制具有重要意义.
刘海林, 主任医师, 上海交通大学医学院附属第九人民医院消化科
ERK信号通路是涉及H. pylori癌蛋白CagA致癌机制的关键信号通路之一, ERK通路的异常激活在胃癌细胞的恶化转化过程中发挥重要作用. 进一步揭示CagA蛋白激活ERK信号通路后的下游分子事件以及ERK通路与其他信号通路的相互作用关系将为CagA蛋白的致癌机制研究提供新的研究证据, 并有望为H. pylori诱发胃癌的分子机制研究提供新思路和新的靶点.
H. pylori被认为是导致胃癌的I类致癌原, 但其诱发胃癌的分子机制尚未阐明. CagA蛋白作为H. pylori的重要毒力因子之一, 可易位进入宿主细胞, 干扰多条信号途径, 发挥其多种生物学作用. 已有研究证实, CagA蛋白可通过激活ERK信号通路对细胞的增殖、凋亡、分散和转移等生物学行为产生影响. 研究CagA蛋白、ERK信号通路与胃癌的关系, 对于揭示H. pylori相关胃癌的分子机制具有重要意义.
本文在分别介绍癌蛋白CagA、ERK信号通路的基础上, 首次比较完整、系统地介绍了目前癌蛋白CagA、ERK信号通路与胃癌关系的主要研究成果.
该文章阐述了目前癌蛋白CagA、ERK信号通路与胃癌关系的主要研究进展, 提出今后要针对CagA激活ERK信号通路后的下游分子事件、对细胞恶性生物学行为的影响、对表观遗传学标志物的作用以及ERK通路与其他信号通路的相互作用关系等展开研究, 以期为进一步揭示H. pylori相关胃癌的分子机制提供重要依据.
本文比较系统地对目前癌蛋白CagA、ERK信号通路与胃癌关系的主要研究成果进行了综述, 使读者对癌蛋白CagA与H. pylori相关胃癌的关系有了进一步的认识, 为H. pylori诱发胃癌的分子机制研究提供了新的思路和新靶点.
编辑:郭鹏 电编:鲁亚静
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