CagA toxin of h pylori associated with gastric cancer is divided into two subtypes: East Asian type (CagAE) and western type (CagAW).

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ABSTRACT​

CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE

 

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Introduction​

Helicobacter pylori is a Gram-negative microaerophilic bacillus that colonizes the stomach [Citation1]. More than 440 million people carry this bacterium [Citation2]. Persistent infection with H. pylori is a precipitating factor in the development of gastric diseases, including chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer (GC) [Citation3]. Numerous studies have revealed a variety of virulence factors in H. pyloridetermining its pathogenicity, including cytotoxin-associated antigen A (CagA), vacuolating cytotoxin (VacA), duodenal ulcer promoting gene A protein (DupA), outer inflammatory protein (OipA), and gamma-glutamyl transpeptidase (GGT) [Citation4]. Among these, CagA is closely associated with carcinogenesis [Citation5].

The molecular weight of CagA ranges from 125 to 145 kDa in different strains [Citation6]. This variation is mainly attributed to the different repetition numbers of the glutamic acid-proline-isoleucine-tyrosine-alanine (EPIYA) motif and the CagA polymeric motif (CM) at its carboxyl-terminal (C-terminal) [Citation5]. Owing to the diversity of its flanking sequence, the EPIYA motif can be categorized into four types: EPIYA-A, -B, -C, and -D [Citation7]. H. pyloristrains popular in East Asian countries such as China, Japan, and Korea possess EPIYA-D, and the arrangement of EPIYA motifs is EPIYA-A-B-D. Prevalent strains in the rest of the world predominantly harbor EPIYA-A-B-C (varying numbers of EPIYA-C, mostly 1–3) [Citation7]. Thus, CagA can be divided into two categories: Western type (CagAW) and East Asian type (CagAE).

 

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Conclusions​

In this study, we found that SHIP2 is an intracellular receptor hijacked by CagA that enhances the carcinogenicity of H. pylori. CagAE exhibited a higher affinity for SHIP2 than CagAW. Depending on this higher affinity, CagAE tethers more SHIP2 to the plasma membrane, produces more PI(3,4)P2, and causes higher activation of Akt signaling, thereby enhancing the neoplastic traits of infected cells. Structural analysis revealed the crucial role of Phe at the Y + 5 position in the EPIYA-D motif, which interacted with the Arg-81 residue of SHIP2-SH2 to establish this higher affinity.

 

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So north east thailand despite eating salt and fermented food still low incidence of stomach cancer (although higher than other parts of Thailand) means genetic and h pylori toxin type are much more important risk factors than salt and fermentation risk factor.