Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA

Rupesh Chaturvedi, Mohammad Asim, Judith Romero-Gallo, Daniel P. Barry, Svea Hoge, Thibaut De Sablet, Alberto G. Delgado, Lydia E. Wroblewski, M. Blanca Piazuelo, Fang Yan, Dawn A. Israel, Robert A. Casero, Pelayo Correa, Alain P. Gobert, D. Brent Polk, Richard M. Peek, Keith T. Wilson

Research output: Contribution to journalArticle

Abstract

Background & Aims: Helicobacter pylori-induced gastric carcinogenesis has been linked to the microbial oncoprotein cytotoxin-associated gene A (CagA). Spermine oxidase (SMO) metabolizes the polyamine spermine into spermidine and generates H2O2, which causes apoptosis and DNA damage. We determined if pathogenic effects of CagA are attributable to SMO. Methods: Levels of SMO, apoptosis, and DNA damage (8-oxoguanosine) were measured in gastric epithelial cell lines infected with cagA+ or cagA- H pylori strains, or transfected with a CagA expression plasmid, in the absence or presence of SMO small interfering RNA, or an SMO inhibitor. The role of CagA in induction of SMO and DNA damage was assessed in H pylori-infected gastritis tissues from humans, gerbils, and both wild-type and hypergastrinemic insulin-gastrin mice, using immunohistochemistry and flow cytometry. Results: cagA+ strains or ectopic expression of CagA, but not cagA- strains, led to increased levels of SMO, apoptosis, and DNA damage in gastric epithelial cells, and knockdown or inhibition of SMO blocked apoptosis and DNA damage. There was increased SMO expression, apoptosis, and DNA damage in gastric tissues from humans infected with cagA+, but not cagA- strains. In gerbils and mice, DNA damage was CagA-dependent and present in cells that expressed SMO. Gastric epithelial cells with DNA damage that were negative for markers of apoptosis accounted for 42%-69% of cells in gerbils and insulin-gastrin mice with dysplasia and carcinoma. Conclusions: By inducing SMO, H pylori CagA generates cells with oxidative DNA damage, and a subpopulation of these cells are resistant to apoptosis and thus at high risk for malignant transformation.

Original languageEnglish (US)
Pages (from-to)1696-1708.e2
JournalGastroenterology
Volume141
Issue number5
DOIs
StatePublished - Nov 2011

Keywords

  • DNA Damage
  • Epithelial Cells
  • Polyamines

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Chaturvedi, R., Asim, M., Romero-Gallo, J., Barry, D. P., Hoge, S., De Sablet, T., Delgado, A. G., Wroblewski, L. E., Piazuelo, M. B., Yan, F., Israel, D. A., Casero, R. A., Correa, P., Gobert, A. P., Polk, D. B., Peek, R. M., & Wilson, K. T. (2011). Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology, 141(5), 1696-1708.e2. https://doi.org/10.1053/j.gastro.2011.07.045