Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells

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, o...

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Vydáno v:	The Journal of clinical investigation Ročník 130; číslo 5; s. 2422 - 2434
Hlavní autoři:	Palrasu, Manikandan, Zaika, Elena, El-Rifai, Wael, Garcia-Buitrago, Monica, Piazuelo, Maria Blanca, Wilson, Keith T., Peek, Richard M., Zaika, Alexander I.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 01.05.2020
Témata:	1-Phosphatidylinositol 3-kinase AKT protein Analysis Antigens, Bacterial - genetics Antigens, Bacterial - metabolism Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Bacteria Bacterial Proteins - genetics Bacterial Proteins - metabolism Binding sites Biodegradation Biomedical research CagA protein Cancer Cells (Biology) Deoxyribonucleic acid Development and progression DNA DNA damage Epithelial cells Epithelial Cells - metabolism Epithelial Cells - microbiology Epithelial Cells - pathology Experiments Gastric cancer Gastric Mucosa - metabolism Gastric Mucosa - microbiology Gastric Mucosa - pathology Gastrointestinal diseases Genetic aspects HCT116 Cells Health aspects Helicobacter infections Helicobacter pylori Helicobacter pylori - genetics Helicobacter pylori - metabolism Homeostasis Humans Infection Infections Kinases Ligases Medical equipment industry Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Phosphorylation Proteasomes Proteins Proteolysis Risk factors Stomach cancer Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Studies Tumor suppressor genes Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase Ubiquitination Virulence (Microbiology) Virulence factors X-Linked Inhibitor of Apoptosis Protein - genetics X-Linked Inhibitor of Apoptosis Protein - metabolism XIAP protein Florida United States Gastric cancer Gastroenterology
ISSN:	0021-9738, 1558-8238, 1558-8238
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI130015