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

Andela Horvat, Jennifer M. Noto, Balamurugan Ramatchandirin, Elena Zaika, Manikandan Palrasu, Jinxiong Wei, Barbara G. Schneider, Wael El-Rifai, Richard M. Peek, Alexander I. Zaika

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5054-5065
Number of pages12
JournalOncogene
Volume37
Issue number37
DOIs
StatePublished - Sep 13 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Horvat, A., Noto, J. M., Ramatchandirin, B., Zaika, E., Palrasu, M., Wei, J., Schneider, B. G., El-Rifai, W., Peek, R. M., & Zaika, A. I. (2018). Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells. Oncogene, 37(37), 5054-5065. https://doi.org/10.1038/s41388-018-0343-8