Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells
Manikandan Palrasu, … , Richard M. Peek Jr., Alexander I. Zaika
Manikandan Palrasu, … , Richard M. Peek Jr., Alexander I. Zaika
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2422-2434. https://doi.org/10.1172/JCI130015.
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Research Article Gastroenterology

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.

Authors

Manikandan Palrasu, Elena Zaika, Wael El-Rifai, Monica Garcia-Buitrago, Maria Blanca Piazuelo, Keith T. Wilson, Richard M. Peek Jr., Alexander I. Zaika

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Figure 1

H.pylori infection leads to downregulation of Siva1.

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H.pylori infection leads to downregulation of Siva1. (A) Representative...
(A) Representative IHC staining for Siva1 protein in the corpus and antrum of uninfected and infected mice. Mice were infected with H. pylori strain PMSS1 for 8 weeks. Scale bars: 50 μm. Insets show magnified views, ×40. Histograms show IHC scores for Siva1 protein expression (n = 8/group). (B) Western blot analysis of Siva1 protein expression in gastric tissues collected from control and infected mice. Bottom panel shows densitometric analysis (n = 3/group). (C) Western blot analyses of Siva1 protein after coculture of AGS cells with H. pylori strains 7.13 and B128 for the indicated time. The graph panel shows quantification of Siva1 protein by densitometry, normalized to actin (n = 3). Expression of Siva1 protein at zero time point was arbitrarily set at 1. Data in A and B were calculated using unpaired 2-tailed t test; data in C were calculated using 1-way ANOVA followed by Tukey’s multiple comparison test. Data are displayed as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001. For additional clarity, A and B are also shown in Figure 8B and Supplemental Figure 8B.