The Pathogenicity Island As a Determinant of Gastric Cancer Risk

Overview

Journal Gut Microbes

Specialties Gastroenterology
Microbiology

Date 2024 Feb 23

PMID 38391242

Authors

Sirena C Tran

Kaeli N Bryant

Timothy L Cover

Affiliations

Soon will be listed here.

Abstract

strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the pathogenicity island ( PAI). Colonization of the human stomach with PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with PAI-negative strains. The PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which strains containing the PAI promote the development of gastric cancer and peptic ulcer disease.

Citing Articles

New perspectives on gastric disorders: the relationship between innate lymphoid cells and microbes in the stomach.

Yan Y, Satoh-Takayama N Cell Mol Life Sci. 2025; 82(1):113.

PMID: 40074935 PMC: 11904066. DOI: 10.1007/s00018-025-05632-w.

Helicobacter pylori and gastric cancer: mechanisms and new perspectives.

Duan Y, Xu Y, Dou Y, Xu D J Hematol Oncol. 2025; 18(1):10.

PMID: 39849657 PMC: 11756206. DOI: 10.1186/s13045-024-01654-2.

Intestinal metaplasia key molecules and UPP1 activation via Helicobacter pylori /NF-kB: drivers of malignant progression in gastric cancer.

Chen X, Zhou B, Wang S, Jiang X, Ping Y, Xia J Cancer Cell Int. 2024; 24(1):399.

PMID: 39695769 PMC: 11657005. DOI: 10.1186/s12935-024-03598-6.

A unique strain to study gastric cancer development.

Whitmire J, Windham I, Makobongo M, Westland M, Tran S, Pinol J Microbiol Spectr. 2024; 13(1):e0216324.

PMID: 39641575 PMC: 11705839. DOI: 10.1128/spectrum.02163-24.

Effects and mechanisms of on cancers development and immunotherapy.

Zhong X, Zheng H, Zhao S, Wang Z, Su Y, Zhong K Front Immunol. 2024; 15:1469096.

PMID: 39434880 PMC: 11491387. DOI: 10.3389/fimmu.2024.1469096.

References

Oliveira M, Costa A, Costa A, Ferreira R, Sampaio P, Machado J . CagA associates with c-Met, E-cadherin, and p120-catenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. J Infect Dis. 2009; 200(5):745-55. DOI: 10.1086/604727. View

Varga M, Wood C, Butt J, Ryan M, You W, Pan K . Immunostimulatory membrane proteins potentiate -induced carcinogenesis by enabling CagA translocation. Gut Microbes. 2020; 13(1):1-13. PMC: 7781638. DOI: 10.1080/19490976.2020.1862613. View

Malfertheiner P, Camargo M, El-Omar E, Liou J, Peek R, Schulz C . Helicobacter pylori infection. Nat Rev Dis Primers. 2023; 9(1):19. PMC: 11558793. DOI: 10.1038/s41572-023-00431-8. View

Wei J, Noto J, Zaika E, Romero-Gallo J, Piazuelo M, Schneider B . Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut. 2014; 64(7):1040-8. PMC: 4312278. DOI: 10.1136/gutjnl-2014-307295. View

Queiroz D, Bittencourt P, Guerra J, Rocha A, Rocha G, Carvalho A . IL1RN polymorphism and cagA-positive Helicobacter pylori strains increase the risk of duodenal ulcer in children. Pediatr Res. 2005; 58(5):892-6. DOI: 10.1203/01.PDR.0000181380.14230.8B. View

Andrzejewska J, Lee S, Olbermann P, Lotzing N, Katzowitsch E, Linz B . Characterization of the pilin ortholog of the Helicobacter pylori type IV cag pathogenicity apparatus, a surface-associated protein expressed during infection. J Bacteriol. 2006; 188(16):5865-77. PMC: 1540075. DOI: 10.1128/JB.00060-06. View

Shibata W, Hirata Y, Maeda S, Ogura K, Ohmae T, Yanai A . CagA protein secreted by the intact type IV secretion system leads to gastric epithelial inflammation in the Mongolian gerbil model. J Pathol. 2006; 210(3):306-14. DOI: 10.1002/path.2040. View

Selbach M, Paul F, Brandt S, Guye P, Daumke O, Backert S . Host cell interactome of tyrosine-phosphorylated bacterial proteins. Cell Host Microbe. 2009; 5(4):397-403. DOI: 10.1016/j.chom.2009.03.004. View

Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T . Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A. 2002; 99(22):14428-33. PMC: 137900. DOI: 10.1073/pnas.222375399. View

10.

Parsonnet J, Friedman G, ORENTREICH N, Vogelman H . Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997; 40(3):297-301. PMC: 1027076. DOI: 10.1136/gut.40.3.297. View

11.

Kuipers E, Perez-Perez G, Meuwissen S, Blaser M . Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst. 1995; 87(23):1777-80. DOI: 10.1093/jnci/87.23.1777. View

12.

Hornsby M, Huff J, Kays R, Canfield D, Bevins C, Solnick J . Helicobacter pylori induces an antimicrobial response in rhesus macaques in a cag pathogenicity island-dependent manner. Gastroenterology. 2008; 134(4):1049-57. PMC: 2386437. DOI: 10.1053/j.gastro.2008.01.018. View

13.

Cover T, Blaser M . Helicobacter pylori in health and disease. Gastroenterology. 2009; 136(6):1863-73. PMC: 3644425. DOI: 10.1053/j.gastro.2009.01.073. View

14.

Queiroz D, Mendes E, Rocha G, Oliveira A, Oliveira C, Magalhaes P . cagA-positive Helicobacter pylori and risk for developing gastric carcinoma in Brazil. Int J Cancer. 1998; 78(2):135-9. DOI: 10.1002/(sici)1097-0215(19981005)78:2<135::aid-ijc1>3.0.co;2-#. View

15.

Javaheri A, Kruse T, Moonens K, Mejias-Luque R, Debraekeleer A, Asche C . Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat Microbiol. 2016; 2:16189. DOI: 10.1038/nmicrobiol.2016.189. View

16.

Tran S, McClain M, Cover T . Role of the CagY antenna projection in Cag type IV secretion system activity. Infect Immun. 2023; 91(9):e0015023. PMC: 10501215. DOI: 10.1128/iai.00150-23. View

17.

Fischer W, Puls J, Buhrdorf R, Gebert B, Odenbreit S, Haas R . Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol. 2002; 42(5):1337-48. DOI: 10.1046/j.1365-2958.2001.02714.x. View

18.

Imai S, Ooki T, Murata-Kamiya N, Komura D, Tahmina K, Wu W . Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe. 2021; 29(6):941-958.e10. DOI: 10.1016/j.chom.2021.04.006. View

19.

Franco A, Israel D, Washington M, Krishna U, Fox J, Rogers A . Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A. 2005; 102(30):10646-51. PMC: 1180811. DOI: 10.1073/pnas.0504927102. View

20.

Tummuru M, Cover T, Blaser M . Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun. 1993; 61(5):1799-809. PMC: 280768. DOI: 10.1128/iai.61.5.1799-1809.1993. View