Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells

Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bact...

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Bibliographic Details
Published in:Oncogene 2018-09, Vol.37 (37), p.5054-5065
Main Authors: Horvat, Andela, Noto, Jennifer M, Ramatchandirin, Balamurugan, Zaika, Elena, Palrasu, Manikandan, Wei, Jinxiong, Schneider, Barbara G, El-Rifai, Wael, Peek, Jr, Richard M, Zaika, Alexander I
Format: Article
Language:English
Subjects:
Antigens, Bacterial - metabolism
Antiulcer agents
Autophagy
Autophagy - physiology
Bacteria
Bacterial Proteins - metabolism
Biodegradation
Cancer
Cancer treatment
Cell Line, Tumor
Down-Regulation - physiology
Epithelial cells
Epithelial Cells - metabolism
Gastric cancer
Gastric mucosa
Gastric Mucosa - metabolism
Gastric Mucosa - pathology
Gene expression
Genetic aspects
HCT116 Cells
Helicobacter infections
Helicobacter Infections - metabolism
Helicobacter Infections - microbiology
Helicobacter pylori
Helicobacter pylori - metabolism
Helicobacter pylori - pathogenicity
Humans
Infection
Ligases
p53 Protein
Pathogens
Phagocytosis
Physiological aspects
Proteins
Risk factors
Signal Transduction - physiology
Stomach - pathology
Stomach cancer
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Tumor proteins
Tumor suppressor genes
Tumor Suppressor Protein p14ARF - metabolism
Tumor Suppressor Protein p53 - metabolism
Tumorigenesis
Tumors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Up-Regulation - physiology
Virulence (Microbiology)
Virulence factors
Virulence Factors - metabolism
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Summary:Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-018-0343-8