p27kip1 deficiency confers susceptibility to gastric carcinogenesis in helicobacter pylori-infected mice

Noriyoshi Kuzushita, Arlin B. Rogers, Nola A. Monti, Mark T. Whary, Min J. Park, Bassam I. Aswad, Haim Shirin, Andrew Koff, Hidetoshi Eguchi, Steven F. Moss

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Abstract

Background & Aims: Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer. Methods: Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later. Results: Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice. Conclusions: p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.

Original languageEnglish
Pages (from-to)1544-1556
Number of pages13
JournalGastroenterology
Volume129
Issue number5
DOIs
Publication statusPublished - Nov 2005

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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    Kuzushita, N., Rogers, A. B., Monti, N. A., Whary, M. T., Park, M. J., Aswad, B. I., Shirin, H., Koff, A., Eguchi, H., & Moss, S. F. (2005). p27kip1 deficiency confers susceptibility to gastric carcinogenesis in helicobacter pylori-infected mice. Gastroenterology, 129(5), 1544-1556. https://doi.org/10.1053/j.gastro.2005.07.056