H. pylori  isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer

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Abstract

Background

H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59.

Methods

One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing.

Results

The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1–6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 ( P < 0.001).

Conclusions

The H. pylori isolates of gastric cancer subjects had a higher rate of HtrA-L171. H. pylori isolates with presence of both HtrA-171 & CagL-Y58/E59 can synergistically increase the risk of gastric cancer.

Electronic supplementary material

The online version of this article (10.1186/s12929-019-0498-9) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.

M F Dixon, R M Genta, J Yardley … (1996)

The Sydney System for the classification of gastritis emphasized the importance of combining topographical, morphological, and etiological information into a schema that would help to generate reproducible and clinically useful diagnoses. To reappraise the Sydney System 4 years after its introduction, a group of gastrointestinal pathologists from various parts of the world met in Houston, Texas, in September 1994. The aims of the workshop were (a) to establish an agreed terminology of gastritis; (b) to identify, define, and attempt to resolve some of the problems associated with the Sydney System. This article introduces the Sydney System as it was revised at the Houston Gastritis Workshop and represents the consensus of the participants. Overall, the principles and grading of the Sydney System were only slightly modified, the grading being aided by the provision of a visual analogue scale. The terminology of the final classification has been improved to emphasize the distinction between the atrophic and nonatrophic stomach; the names used for each entity were selected because they are generally acceptable to both pathologists and gastroenterologists. In addition to the main categories and atrophic and nonatrophic gastritis, the special or distinctive forms are described and their respective diagnostic criteria are provided. The article includes practical guidelines for optimal biopsy sampling of the stomach, for the use of the visual analogue scales for grading the histopathologic features, and for the formulation of a comprehensive standardized diagnosis. A glossary of gastritis-related terms as used in this article is provided.

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Helicobacter exploits integrin for type IV secretion and kinase activation.

Terry Kwok, Dana Zabler, Sylwia Urman … (2007)

Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha5beta1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.

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Is Open Access

Helicobacter pylori Diversity and Gastric Cancer Risk

Timothy Cover (2016)

ABSTRACT Gastric cancer is a leading cause of cancer-related death worldwide. Helicobacter pylori infection is the strongest known risk factor for this malignancy. An important goal is to identify H. pylori-infected persons at high risk for gastric cancer, so that these individuals can be targeted for therapeutic intervention. H. pylori exhibits a high level of intraspecies genetic diversity, and over the past two decades, many studies have endeavored to identify strain-specific features of H. pylori that are linked to development of gastric cancer. One of the most prominent differences among H. pylori strains is the presence or absence of a 40-kb chromosomal region known as the cag pathogenicity island (PAI). Current evidence suggests that the risk of gastric cancer is very low among persons harboring H. pylori strains that lack the cag PAI. Among persons harboring strains that contain the cag PAI, the risk of gastric cancer is shaped by a complex interplay among multiple strain-specific bacterial factors as well as host factors. This review discusses the strain-specific properties of H. pylori that correlate with increased gastric cancer risk, focusing in particular on secreted proteins and surface-exposed proteins, and describes evidence from cell culture and animal models linking these factors to gastric cancer pathogenesis. Strain-specific features of H. pylori that may account for geographic variation in gastric cancer incidence are also discussed.

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Author and article information

Contributors

Yi-Chun Yeh: yehyichun0110@gmail.com

Hsin-Yu Kuo: Telomere-aging@hotmail.com.tw

Wei-Lun Chang: weilun1@mail.ncku.edu.tw

Hsiao-Bai Yang: hbyang@tyh.com.tw

Cheng-Chan Lu: cclu@mail.ncku.edu.tw

Hsiu-Chi Cheng: teishuki@mail.ncku.edu.tw

Ming-Shiang Wu: ntudopcm@ntu.edu.tw

Bor-Shyang Sheu: +886-6-2353535 , sheubs@mail.ncku.edu.tw

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central (London )

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date (Electronic): 5 January 2019

Publication date PMC-release: 5 January 2019

Publication date Collection: 2019

Volume: 26

Electronic Location Identifier: 4

Affiliations

[1 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Internal Medicine, National Cheng Kung University Hospital, , College of Medicine, National Cheng Kung University, ; Tainan, Taiwan

[2 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Institute of Clinical Medicine, College of Medicine, , National Cheng Kung University, ; Tainan, Taiwan

[3 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Pathology, National Cheng Kung University Hospital, , College of Medicine, National Cheng Kung University, ; Tainan, Taiwan

[4 ]Department of Pathology, Ton Yen General Hospital, Hsin-Chu, Taiwan

[5 ]GRID grid.454740.6, Department of Internal Medicine, Tainan Hospital, , Ministry of Health and Welfare, ; 125 Chuang Shan Road, Tainan, Taiwan

[6 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Department of Internal Medicine, National Taiwan University Hospital, , College of Medicine, National Taiwan University, ; Taipei, Taiwan

Article

Publisher ID: 498

DOI: 10.1186/s12929-019-0498-9

PMC ID: 6321681

PubMed ID: 30611258

SO-VID: d1caa3d3-c17a-4d47-af56-b18f8aed620a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 May 2018

Date accepted : 2 January 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100007225, Ministry of Science and Technology;

Award ID: MOST-104-2314-B-006-025-MY3

Award Recipient : Bor-Shyang Sheu

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ScienceOpen disciplines: Molecular medicine

Keywords: gastric cancer,h. pylori,htra,cagl,type iv secretory system

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ScienceOpen disciplines: Molecular medicine

Keywords: gastric cancer, h. pylori, htra, cagl, type iv secretory system

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H. pylori isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer

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Electronic supplementary material

Related collections

When did Helicobacter first colonise humans?

Most cited references 29

Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.

Helicobacter exploits integrin for type IV secretion and kinase activation.

Helicobacter pylori Diversity and Gastric Cancer Risk

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Cited by 9

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