幽门螺杆菌参与胃癌侵袭转移的研究进展

doi:10.3969/j.issn.1674-8115.2023.04.013

摘要/Abstract

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.

Key words: stomach neoplasm, Helicobacter pylori, CagA protein, VacA protein, neoplasm metastasis, immune escape

中图分类号:

R735.2

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[J]. 上海交通大学学报（医学版）, 2023, 43(4): 495-499.

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

参考文献 42

1	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
2	THRIFT A P, EL-SERAG H B. Burden of gastric cancer[J]. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542.
3	JOSHI S S, BADGWELL B D. Current treatment and recent progress in gastric cancer[J]. CA Cancer J Clin, 2021, 71(3): 264-279.
4	ANSARI S, YAMAOKA Y. Helicobacter pylori virulence factors exploiting gastric colonization and its pathogenicity[J]. Toxins, 2019, 11(11): 677.
5	YANG Y H, SHU X, XIE C. An overview of autophagy in Helicobacter pylori infection and related gastric cancer[J]. Front Cell Infect Microbiol, 2022, 12: 847716.
6	HOOI J K Y, LAI W Y, NG W K, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis[J]. Gastroenterology, 2017, 153(2): 420-429.
7	WARREN J R, MARSHALL B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis[J]. Lancet, 1983, 1(8336): 1273-1275.
8	MAIXNER F, KRAUSE-KYORA B, TURAEV D, et al. The 5300-year-old Helicobacter pylori genome of the iceman[J]. Science, 2016, 351(6269): 162-165.
9	HUANG Y, WANG Q L, CHENG D D, et al. Adhesion and invasion of gastric mucosa epithelial cells by Helicobacter pylori[J]. Front Cell Infect Microbiol, 2016, 6: 159.
10	ILVER D, ARNQVIST A, OGREN J, et al. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging[J]. Science, 1998, 279(5349): 373-377.
11	KÖNIGER V, HOLSTEN L, HARRISON U, et al. Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA[J]. Nat Microbiol, 2016, 2: 16188.
12	YAMAOKA Y, KITA M, KODAMA T, et al. Helicobacter pylori infection in mice: role of outer membrane proteins in colonization and inflammation[J]. Gastroenterology, 2002, 123(6): 1992-2004.
13	MAHDAVI J, SONDÉN B, HURTIG M, et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation[J]. Science, 2002, 297(5581): 573-578.
14	WANG F, MENG W, WANG B, et al. Helicobacter pylori-induced gastric inflammation and gastric cancer[J]. Cancer Lett, 2014, 345(2): 196-202.
15	AMIEVA M, PEEK R M Jr. Pathobiology of Helicobacter pylori-induced gastric cancer[J]. Gastroenterology, 2016, 150(1): 64-78.
16	NEJATI S, KARKHAH A, DARVISH H, et al. Influence of Helicobacter pylori virulence factors CagA and VacA on pathogenesis of gastrointestinal disorders[J]. Microb Pathog, 2018, 117: 43-48.
17	CAPURRO M I, GREENFIELD L K, PRASHAR A, et al. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1[J]. Nat Microbiol, 2019, 4(8): 1411-1423.
18	CHMIELA M, KARWOWSKA Z, GONCIARZ W, et al. Host pathogen interactions in Helicobacter pylori related gastric cancer[J]. World J Gastroenterol, 2017, 23(9): 1521-1540.
19	TAKAHASHI-KANEMITSU A, KNIGHT C T, HATAKEYAMA M. Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis[J]. Cell Mol Immunol, 2020, 17(1): 50-63.
20	COVER T L. Helicobacter pylori diversity and gastric cancer risk[J]. mBio, 2016, 7(1): e01869-e01815.
21	NISHIKAWA H, HATAKEYAMA M. Sequence polymorphism and intrinsic structural disorder as related to pathobiological performance of the Helicobacter pylori CagA oncoprotein[J]. Toxins, 2017, 9(4): 136.
22	HATAKEYAMA M. SagA of CagA in Helicobacter pylori pathogenesis[J]. Curr Opin Microbiol, 2008, 11(1): 30-37.
23	STEIN M, RAPPUOLI R, COVACCI A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation[J]. Proc Natl Acad Sci USA, 2000, 97(3): 1263-1268.
24	MUELLER D, TEGTMEYER N, BRANDT S, et al. C-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains[J]. J Clin Invest, 2012, 122(4): 1553-1566.
25	LIU B, LI X K, SUN F Z, et al. HP-CagA+ regulates the expression of CDK4/CyclinD1 via reg3 to change cell cycle and promote cell proliferation[J]. Int J Mol Sci, 2019, 21(1): 224.
26	SEGAL E D, CHA J, LO J, et al. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori[J]. Proc Natl Acad Sci USA, 1999, 96(25): 14559-14564.
27	BESSÈDE E, STAEDEL C, ACUÑA AMADOR L A, et al. Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes[J]. Oncogene, 2014, 33(32): 4123-4131.
28	NAGY T A, FREY M R, YAN F, et al. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling[J]. J Infect Dis, 2009, 199(5): 641-651.
29	HIGASHI H, TSUTSUMI R, MUTO S, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein[J]. Science, 2002, 295(5555): 683-686.
30	TENG Y S, CHEN W Y, YAN Z B, et al. L-plastin promotes gastric cancer growth and metastasis in a Helicobacter pylori cagA-ERK-SP1-dependent manner[J]. Mol Cancer Res, 2021, 19(6): 968-978.
31	YANG F H, XU Y G, LIU C, et al. NF-κB/miR-223-3p/ARID1A axis is involved in Helicobacter pylori CagA-induced gastric carcinogenesis and progression[J]. Cell Death Dis, 2018, 9(1): 12.
32	JIANG X J, WANG J, DENG X Y, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape[J]. Mol Cancer, 2019, 18(1): 10.
33	DEBERARDINIS R J. Tumor microenvironment, metabolism, and immunotherapy[J]. N Engl J Med, 2020, 382(9): 869-871.
34	ZHAO L, LIU Y Y, ZHANG S M, et al. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer[J]. Cell Death Dis, 2022, 13(4): 378.
35	SUN C, MEZZADRA R, SCHUMACHER T N. Regulation and function of the PD-L1 checkpoint[J]. Immunity, 2018, 48(3): 434-452.
36	DAS S, SUAREZ G, BESWICK E J, et al. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection[J]. J Immunol, 2006, 176(5): 3000-3009.
37	DENG R Y, ZHENG H L, CAI H Z, et al. Effects of Helicobacter pylori on tumor microenvironment and immunotherapy responses[J]. Front Immunol, 2022, 13: 923477.
38	BAJ J, KORONA-GŁOWNIAK I, FORMA A, et al. Mechanisms of the epithelial-mesenchymal transition and tumor microenvironment in Helicobacter pylori-induced gastric cancer[J]. Cells, 2020, 9(4): 1055.
39	ZAVROS Y, MERCHANT J L. The immune microenvironment in gastric adenocarcinoma[J]. Nat Rev Gastroenterol Hepatol, 2022, 19(7): 451-467.
40	BAJ J, BRZOZOWSKA K, FORMA A, et al. Immunological aspects of the tumor microenvironment and epithelial-mesenchymal transition in gastric carcinogenesis[J]. Int J Mol Sci, 2020, 21(7): 2544.
41	LEE K, HWANG H, NAM K T. Immune response and the tumor microenvironment: how they communicate to regulate gastric cancer[J]. Gut Liver, 2014, 8(2): 131-139.
42	HOLOKAI L, CHAKRABARTI J, BRODA T, et al. Increased programmed death-ligand 1 is an early epithelial cell response to Helicobacter pylori infection[J]. PLoS Pathog, 2019, 15(1): e1007468.

[1]	崔锡炜, 钟民衎, 热汗姑丽·艾买尔, 王智超, 李青峰. 人多效蛋白抑制恶性周围神经鞘瘤转移的机制研究[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1225-1238.
[2]	张修齐, 沈柏用. 胰腺导管腺癌神经侵袭的细胞学机制研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(6): 833-838.
[3]	戚炀炀, 熊鹰. Galectin-9阳性肿瘤相关巨噬细胞在肌层浸润性膀胱癌中的表型、功能及临床治疗意义[J]. 上海交通大学学报（医学版）, 2022, 42(12): 1666-1676.
[4]	刘梦珂, 纪濛濛, 程林, 黄金艳, 孙晓建, 赵维莅, 王黎. 黄芩苷抗肿瘤作用机制的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(2): 246-250.
[5]	徐忠匀，吴书其，王少雁，王丹阳，傅宏亮. 131I治疗分化型甲状腺癌伴肺转移的效果评价及其影响因素分析[J]. 上海交通大学学报（医学版）, 2019, 39(4): 412-.
[6]	范霞 1，夏碧丽 2，吕霖 1，徐梦莎 3，李佳茵 1，何平 1. 小鼠巨噬细胞对钩端螺旋体 56606v和 56606a的吞噬及炎症应答的比较研究[J]. 上海交通大学学报（医学版）, 2019, 39(1): 16-.
[7]	赵巧云，谢勇. 幽门螺杆菌外膜蛋白与黏附机制的研究进展[J]. 上海交通大学学报（医学版）, 2017, 37(2): 249-.
[8]	龚进发，董媛媛*，张义，王玥，董伟，罗梦云，莫丹丹，张智若 . 上海市1 960例船员幽门螺杆菌感染情况分析[J]. 上海交通大学学报（医学版）, 2017, 37(1): 102-.
[9]	汪成，洪晏，余燕民，等. 肿瘤转移相关蛋白3与乳腺癌预后的相关性研究[J]. 上海交通大学学报（医学版）, 2016, 36(2): 195-.
[10]	刘博，邱纯，李鹏，等. 靶向敲除JARID2基因对葡萄膜黑色素瘤细胞生长与转移的影响[J]. 上海交通大学学报（医学版）, 2015, 35(5): 642-.
[11]	史浩骏，王志刚. 长链非编码RNA肺腺癌转移相关转录本1及其在肿瘤转移中的作用[J]. 上海交通大学学报（医学版）, 2014, 34(8): 1254-.
[12]	徐枫，席云，张敏，等. ¹⁸F-FDG PET/CT对腹部增强CT术前评估胰腺癌远处转移的增益价值[J]. 上海交通大学学报（医学版）, 2014, 34(12): 1762-.
[13]	朱时燕，徐雷鸣. 左氧氟沙星为基础的三联疗法根除幽门螺杆菌的meta分析[J]. 上海交通大学学报（医学版）, 2014, 34(12): 1780-.
[14]	郑雄，李健，孙颖，等. 133例胃癌患者的超声内镜术前分期结果分析[J]. 上海交通大学学报（医学版）, 2014, 34(10): 1516-.
[15]	朱博, 宋超, 王萍. ID1蛋白在胃癌组织中的表达及临床意义[J]. , 2013, 33(3): 298-.