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

Gastroenterology. 2011 Nov;141(5):1696-708.e1-2. doi: 10.1053/j.gastro.2011.07.045. Epub 2011 Aug 10.

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 H(2)O(2), 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / metabolism*
  • Apoptosis / physiology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Line
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • DNA Damage / physiology
  • Disease Models, Animal
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / microbiology
  • Gastric Mucosa / metabolism*
  • Gerbillinae
  • Helicobacter Infections / complications
  • Helicobacter Infections / metabolism
  • Helicobacter pylori / isolation & purification
  • Helicobacter pylori / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / physiology
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism*
  • Risk Factors
  • Stomach / cytology
  • Stomach / microbiology
  • Stomach Neoplasms / epidemiology*
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • cagA protein, Helicobacter pylori
  • Oxidoreductases Acting on CH-NH Group Donors
  • polyamine oxidase

Grant support