Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells

Abstract

Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.

Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis

“…Interestingly, the dysregulation of p53 occurs in a strain-specific manner, with tumorigenic H. pylori strains having a stronger ability to affect p53 [ 40 , 43 ]. Tumorigenic H. pylori strains also decrease activity of other tumor suppressors: p14ARF, SIVA1, and p27(KIP1) [ 43 , 44 , 45 , 46 ].…”

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…Recurrent bacterial, viruses and fungal infections are some of the major factors. Chronic inflammation triggered by persistence of H. pylori is often preceding gastric cancer appearance ( 277 – 279 ), a phenomenon drastically worsened in some PID patients ( 280 , 281 ). Similar observations were made for fungal infections ( 282 ) or for the Epstein Barr Virus, as recently highlighted in another special issue of Frontiers In Immunology ( 283 ).…”

Helicobacter pylori Virulence Factor Cytotoxin-Associated Gene A (CagA)-Mediated Gastric Pathogenicity

“…A recent study demonstrated that the H. pylori virulence factor CagA could influence the Siva1 protein via increasing ubiquitination and proteasomal degradation mediated by the activation of the PI3K/Akt pathway and XIAP E3 ubiquitin ligase [ 110 ]. The data also suggested a downregulation of Siva1, causing inhibition of the apoptotic and DNA damage responses induced by H. pylori , whereas CagA was found to inhibit the apoptotic cell death promoting the survival of damaged epithelial cells that contributes to gastric tumorigenesis [ 110 ].…”