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

Oncogene volume 37, pages 5054–5065 (2018)Cite this article

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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.

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Acknowledgements

We thank Drs. Maria B. Piazuelo and Alberto G. Delgado for help with tissue processing. This work was supported by grants from the National Cancer Institute CA206564, R01 CA138833, the Department of Veterans Affairs BX002115, Vanderbilt Ingram Cancer Center (P30 CA68485), and the Vanderbilt Digestive Disease Research Center (DK058404). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, National Institutes of Health, Vanderbilt University, or University of Miami Health Centers.

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Authors and Affiliations

  1. Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Andela Horvat, Balamurugan Ramatchandirin, Jinxiong Wei & Alexander I. Zaika

  2. Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, USA

    Jennifer M. Noto, Barbara G. Schneider & Richard M. Peek Jr

  3. Department of Surgery, University of Miami, Miami, FL, USA

    Elena Zaika, Manikandan Palrasu, Wael El-Rifai & Alexander I. Zaika

  4. Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, USA

    Alexander I. Zaika

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  1. Andela Horvat
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Correspondence to Alexander I. Zaika.

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Horvat, A., Noto, J.M., Ramatchandirin, B. et al. Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells. Oncogene 37, 5054–5065 (2018). https://doi.org/10.1038/s41388-018-0343-8

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  • DOI: https://doi.org/10.1038/s41388-018-0343-8

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