上海交通大学学报（医学版）

上海交通大学学报(医学版), 2023, 43(4): 495-499 doi: 10.3969/j.issn.1674-8115.2023.04.013

综述

幽门螺杆菌参与胃癌侵袭转移的研究进展

肖蓉,, 陶双芬, 陈思宇, 郑磊贞, 朱美玲,

上海交通大学医学院附属新华医院肿瘤科，上海 200092

Advances in Helicobacter pylori infection involved in gastric cancer metastasis

XIAO Rong,, TAO Shuangfen, CHEN Siyu, ZHENG Leizhen, ZHU Meiling,

Department of Oncology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

通讯作者: 朱美玲，电子信箱：zhumeiling@xinhuamed.com.cn。

编委: 邵碧云

收稿日期: 2022-09-01   接受日期: 2023-03-15   网络出版日期: 2023-04-28

基金资助: 上海市浦江人才计划.  2019PJD034

Corresponding authors: ZHU Meiling, E-mail:zhumeiling@xinhuamed.com.cn.

Received: 2022-09-01   Accepted: 2023-03-15   Online: 2023-04-28

作者简介 About authors

肖蓉（1998—），女，硕士生；电子信箱：xrolive98@126.com。 E-mail：xrolive98@126.com。

摘要

胃癌（gastric cancer，GC）是一种常见的消化道癌症，在东亚和东南亚人群中高发。全球大约有50%以上的人口感染幽门螺杆菌（Helicobacter pylori，HP），HP感染已被证实是GC的致病因素之一，与GC的发生有着密切的关联，与GC侵袭转移的关系虽尚无定论但也有了一定的研究进展。一方面，HP定植胃黏膜后，通过其关键毒力因子空泡细胞毒素A （vacuolating cytotoxin A，VacA）和细胞毒素相关抗原A（cytotoxin-associated antigen A，CagA）的作用使其得以长期存活于胃内，并参与GC细胞的增殖、上皮‒间质转化来促进侵袭转移；另一方面，肿瘤微环境作为宿主免疫系统与肿瘤相互作用的场所，HP通过干扰肿瘤微环境内肿瘤细胞与免疫细胞的相互作用、促进肿瘤微环境酸性缺氧环境的形成以及改变微环境内细胞分化等方式，促使GC免疫逃逸从而促进GC的侵袭转移。HP感染如今已成为一个全球性的公共卫生问题，对于GC发生发展的作用更是不容忽视。该文主要围绕上述2个方面，即关键毒力因子和肿瘤微环境来阐述HP感染与GC侵袭转移的相关性，期望能为GC的临床和基础研究提供新思路。

关键词： 胃肿瘤 ; 幽门螺杆菌 ; CagA蛋白 ; VacA蛋白 ; 肿瘤转移 ; 免疫逃逸

Abstract

Gastric cancer is a common cancer of the gastrointestinal tract, highly occurring in East and Southeast Asian. Roughly more than 50% of the population is exposed to Helicobacter pylori (H. pylori) infection worldwide. H. pylori infection is one of the risk factors for gastric cancer and is strongly associated with the development of gastric cancer. The association between H. pylori infection and metastasis of gastric cancer is still inconclusive but has made some progress. For one thing, H. pylori is colonized in the gastric mucosa. The effect of its key virulence factors, VacA and CagA proteins, keeps H. pylori alive in the stomach for a long time and makes it possible for H. pylori to promote the proliferation, epithelial-mesenchymal transition and metastasis of gastric cancer cells. For another, the tumor microenvironment is the site of interaction between host immune system and tumor. By interfering with the effect of tumor cells and immune cells, enhancing the formation of an acidic and hypoxic environment and altering the differentiation of cells in the tumor microenvironment, H. pylori infection can strengthen immune escape and then facilitate the metastasis of gastric cancer. H. pylori infection has become a global public health problem, and its influence on the evolution of gastric cancer cannot be disregarded. The review addresses the correlation between H. pylori infection and gastric cancer metastasis through both key virulence factors and tumor microenvironment. It will provide reference for clinical and basic research in gastric cancer.

Keywords： stomach neoplasm ; Helicobacter pylori ; CagA protein ; VacA protein ; neoplasm metastasis ; immune escape

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肖蓉, 陶双芬, 陈思宇, 郑磊贞, 朱美玲. 幽门螺杆菌参与胃癌侵袭转移的研究进展. 上海交通大学学报(医学版)[J], 2023, 43(4): 495-499 doi:10.3969/j.issn.1674-8115.2023.04.013

XIAO Rong, TAO Shuangfen, CHEN Siyu, ZHENG Leizhen, ZHU Meiling. Advances in Helicobacter pylori infection involved in gastric cancer metastasis. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(4): 495-499 doi:10.3969/j.issn.1674-8115.2023.04.013

胃癌（gastric cancer，GC）是全球第五大常见癌症，也是癌症第四大死亡原因［1］。GC发病率存在一定的地域差异，GC发病总人数的60%以上分布在东亚和东南亚地区，其中东亚地区GC发病率最高［2］。幽门螺杆菌（Helicobacter pylori，HP）感染、年龄较大、过度食用腌制食品、GC家族史、吸烟、胃手术史等是GC发病常见的危险因素［3］。HP感染除了影响GC的发生，也可能促进GC的进展转移［4］。本文主要从HP关键毒力因子和肿瘤微环境（tumor microenvironment，TME）2个方面对HP促进GC侵袭转移的机制展开论述，旨在为GC的基础研究乃至临床治疗提供新思路。

1 HP定植

全球大约有超过50%以上的人口感染HP［5］。它是一种革兰阴性、有鞭毛的螺旋状细菌，由MARSHALL和WARREN发现，可感染胃上皮细胞［6-7］。HP与人类共存寄生的数十万年中［8］，在胃内已经形成了较为成熟的定植机制：首先，HP经黏蛋白黏附于胃上皮黏液层，通过分泌尿素酶催化尿素水解生成氨中和胃酸，形成有利于HP生存的微环境；随之，通过鞭毛运动穿过黏液层到达胃上皮细胞［4，9］；最后，HP外膜蛋白（outer membrane proteins，OMPs）中的黏附素成分通过HP自身分泌 BabA、SabA、HopZ、HopQ、OipA等黏附素黏附于宿主胃上皮细胞［10-13］。以上过程使HP得以成功定植于宿主细胞，并且能够抵抗胃内流体动力的物理清除。虽然HP的定植通常不会引起临床表现，但在受感染的个体中，大约10%的患者会发展为消化性溃疡病，1%~3%发展为GC，0.1%发展为黏膜相关淋巴组织（mucosa-associated lymphoid tissue，MALT）淋巴瘤［14］。所以HP的定植是其发挥致病力的基础。

2 HP毒力因子对GC侵袭的作用

目前，对GC的发生发展起作用的HP毒力因子主要包括空泡细胞毒素A（vacuolating cytotoxin A，VacA）、细胞毒素相关抗原A（cytotoxin-associated antigen A，CagA）及其与之相关的Ⅳ型分泌系统（type Ⅳ secretion system，T4SS）［15］。

几乎所有HP都存在VacA基因，并且VacA可能是HP深入定植和易复发感染的原因之一。VacA是一种成孔细胞毒素，由细菌V型自转运分泌系统分泌，并通过内吞作用进入宿主细胞［16］。CAPURRO等［17］通过小鼠模型对VacA展开相关研究，发现VacA靶向溶酶体钙离子通道TRPML1来破坏内溶酶体运输，从而篡夺了溶酶体和自噬途径，产生一个保护性的细胞内生态位，使HP逃脱抗生素的作用，最终得以在胃内存活，持续刺激宿主细胞。VacA包含s、i、d、m 4个已识别的可变区，VacA的s1/m1等位基因决定了VacA的高毒性，相比之下，s1/m2和s2/m2基因型没有细胞毒性，s1/m1谱系与肿瘤发生进展以及GC的结局有一定的关联［18］。

CagA阳性菌株的慢性感染被认为是GC发生发展的最强危险因素［19］，相较于VacA，对于GC进展的毒力作用更强。一部分HP菌株含有一个大约40 kb的染色体DNA区域，称为Cag致病岛（cag pathogenicity island，Cag PAI）［20］。值得注意的是，几乎所有东亚HP菌株都含Cag致病岛，然而在西方国家，只有约60%菌株含有Cag致病岛［21］，这也许是东亚人群较西方人群GC高发的原因之一。Cag致病岛编码细菌T4SS的主要结构成分以及CagA［22］。CagA存在于HP胞质中，最终通过T4SS转运进入宿主细胞［23］。CagA到达宿主细胞的胞质溶胶后，其谷氨酸‒脯氨酸‒异亮氨酸‒酪氨酸‒丙氨酸（glutamate-proline-isoleucine-tyrosine-alanine，EPIYA）基序中的酪氨酸就会被宿主的c-SRC和c-ABL激酶磷酸化［24］，随之CagA作为真核生物信号枢纽发挥作用。

CagA有促进GC细胞增殖、上皮‒间质转化（epithelial-mesenchymal transition，EMT）和侵袭转移的能力。有研究提示，CagA阳性的HP通过宿主胃黏膜组织中的再生基因-3（regeneration gene 3，Reg3）调节CDK4/CyclinD1的表达，以改变细胞周期、促进细胞增殖［25］。EMT是指细胞极性和连接丧失，逐渐获得间质细胞特性的过程，EMT参与癌症侵袭和转移。CagA可以改变细胞表型，这是胃上皮细胞产生蜂鸟表型所必需的［26］。另一项研究［27］也表明，胃上皮细胞感染CagA阳性的HP之后，EMT相关标志物（Snail1、Vimentin和ZEB1等）上调，上皮细胞相关标志物角蛋白-7（cytokeratin 7，CK7）和骨桥蛋白（osteopontin）下调，而且感染导致胃上皮细胞迁移和侵袭的能力增加。除此之外，CagA也可以通过激活多种信号通路作用于胃上皮细胞，比如通过激活磷脂酰肌醇3-激酶/蛋白激酶B（phosphatidylinositol 3-kinase/protein kinase B，PI3K/PKB）信号，进而抑制胃上皮细胞凋亡并促进其迁移［28］；磷酸化的CagA与含Src同源2结构域蛋白酪氨酸磷酸酶（the SRC homology 2 domain-containing tyrosine phosphatase，SHP-2）的结合可能诱发胃上皮细胞的异常增殖以及促进获得细胞转化的表型［29］；CagA可以激活细胞外调节蛋白激酶（extracellular regulated protein kinases，ERK）信号通路，介导转录因子SP1（specificity protein 1，SP1）与L-plastin启动子结合进而增强L-plastin的表达，从而促进GC细胞增殖和转移等［30］。CagA阳性的HP也可通过促进微RNA（microRNA，miRNA）表达而实现促癌作用，有研究提示CagA阳性的HP可通过核因子κB（nuclear factor-κB，NF-κB）结合miR-223-3p启动子刺激miR-223-3p的表达，miR-223-3p通过直接靶向ARID1A并降低其表达来促进GC细胞的增殖和迁移［31］。

3 HP介导GC免疫逃逸

免疫逃逸（immune escape）一直是免疫治疗领域的难题。肿瘤细胞的低免疫原性、肿瘤特异性抗体作为自身抗原的识别、肿瘤表面抗原调节、肿瘤诱导的豁免区域和肿瘤诱导的免疫抑制是肿瘤发生免疫逃逸的诱导因素，其中免疫抑制是迄今为止研究最广泛的机制［32］。GC免疫抑制的发生与其所在的TME密不可分。免疫细胞、成纤维细胞、细胞外基质和各种细胞因子等成分，构成了TME的复杂网络［33］。作为宿主免疫系统与肿瘤细胞相互作用的一个场所，它的变化影响着肿瘤的发展方向、关系着GC的预后。HP作为经典的胃内生存菌株，也参与了胃肿瘤微环境的调节。当HP长期存在于胃肿瘤细胞时，细胞产生的乳酸、腺苷、一氧化氮等代谢副产物大量堆积，形成一个酸性缺氧的TME，进而抑制被募集进入TME的免疫细胞功能，增加肿瘤转移的可能性［34］。

不止于此，HP对于TME中的细胞和免疫检查点的影响也关乎GC患者的病情走向。肿瘤细胞表面程序性死亡配体-1（programmed cell death legand 1，PD-L1）与T细胞的程序性死亡受体-1（programmed cell death protein-1，PD-1）结合后，可抑制T细胞的激活信号、诱导T细胞凋亡，从而削弱宿主抗肿瘤免疫反应，实现免疫逃逸［35］。有文章提出，HP与GC细胞PD-L1的表达呈正相关，HP感染可通过激活p38丝裂原活化蛋白激酶（p38 mitogen-activated protein kinase，p38 MAPK）通路、雷帕霉素复合物1（mechanistic target of rapamycin complex 1，mTORC1）信号通路等途径上调GC细胞PD-L1的表达，抑制T细胞增殖并诱导幼稚T细胞向Treg细胞分化，从而逃避免疫监视、促进免疫逃逸，最终导致病情进展［36-37］。HP感染也可导致成纤维细胞和肌成纤维细胞转化为恶性肿瘤相关成纤维细胞（cancer-associated fibroblasts，CAFs），CAFs随即释放白细胞介素-6（interleukin-6，IL-6）、环氧合酶-2（COX-2）、趋化因子配体-1［chemokine（C-X-C motif）ligand 1，CXCL1］、CXCL9等物质促进EMT、细胞迁移和侵袭［38］。由于树突状细胞（dendritic cells，DCs）和其他免疫细胞表达吲哚胺2, 3-双加氧酶1（indoleamine 2, 3-dioxygenase 1，IDO1），肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）作为一种肿瘤抑制细胞，在HP形成慢性炎症之初就已经存在于胃免疫微环境之中［39］。TAMs的高度浸润被证实与GC侵袭迁移有关，TAMs可通过激活β-catenin通路、诱导叉头框蛋白Q1（forkhead box Q1，FOXQ1）表达以及分泌IL-10等方式促进这一作用，同时也通过转化生长因子-β（transforming growth factor-β，TGF-β）致NK细胞功能受损而间接达到目的［40］。在实体恶性肿瘤中，TAMs分为M1型和M2型，M2型巨噬细胞的积累通常被认为与肿瘤预后不良有关，而M1型巨噬细胞的浸润可引发针对肿瘤的保护性免疫反应［41］。另外，研究还发现，HP依赖于CagA，可通过胃上皮内的sonic hedgehog（Shh）信号通路显著增加类器官中PD-L1的表达［42］。

4 总结与展望

现今HP与GC发生的相关性研究有了里程碑意义的进展，但是HP对于GC侵袭转移的作用和影响，还需进一步挖掘和探索。相较于欧美HP菌株，几乎所有的东亚HP菌株都含Cag致病岛，Cag致病岛编码的CagA可促进GC上皮‒间质转化以及转移，所以包括中国在内的整个东亚的HP感染问题应得到持续重视。并且HP具有通过改变TME促进GC发生免疫逃逸的潜能。以上因素均可能对GC患者的治疗效果以及生存期产生不利影响。

总之，HP促进GC侵袭转移的通路、细胞是复杂且庞大的，仍有许多尚未解决的问题。随着相关研究的不断深入，HP参与GC侵袭转移的更多机制将被揭开。

作者贡献声明

肖蓉负责文献检索、论文撰写、论文修改；陶双芬负责文献检索、论文指导、论文修改；陈思宇负责论文指导、文献检索、论文修改；郑磊贞负责论文指导、文献检索、论文修改；朱美玲负责论文构思和指导、论文修改、定稿。所有作者均阅读并同意了最终稿件的提交。

AUTHOR's CONTRIBUTIONS

XIAO Rong was responsible for literature search, writing the review, and paper revision. TAO Shuangfen was in charge of literature search, writing guidance, and revising article. CHEN Siyu was in charge of literature search, writing guidance, and revising article. ZHENG Leizhen was accountable for literature search, writing guidance, and revising article. ZHU Meiling was responsible for conceptualizing and directing the review, and then revising and finalizing it. All the authors have read the last version of paper and consented for submission.

利益冲突声明

所有作者声明不存在利益冲突。

COMPETING INTERESTS

All authors disclose no relevant conflict of interests.

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