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

Research output: Contribution to journalArticle

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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 - Jan 1 2005
Externally publishedYes

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Helicobacter pylori
Stomach
Carcinogenesis
Pylorus
Stomach Neoplasms
Metaplasia
Infection
Carcinogenicity Tests
Apoptosis
Cyclin-Dependent Kinases
Inbred C57BL Mouse
Carcinogens
Hyperplasia
Neoplasms
Inflammation

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Kuzushita, N., Rogers, A. B., Monti, N. A., Whary, M. T., Park, M. J., Aswad, B. I., ... 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

p27kip1 deficiency confers susceptibility to gastric carcinogenesis in helicobacter pylori-infected mice. / Kuzushita, Noriyoshi; Rogers, Arlin B.; Monti, Nola A.; Whary, Mark T.; Park, Min J.; Aswad, Bassam I.; Shirin, Haim; Koff, Andrew; Eguchi, Hidetoshi; Moss, Steven F.

In: Gastroenterology, Vol. 129, No. 5, 01.01.2005, p. 1544-1556.

Research output: Contribution to journalArticle

Kuzushita, N, Rogers, AB, Monti, NA, Whary, MT, Park, MJ, Aswad, BI, Shirin, H, Koff, A, Eguchi, H & Moss, SF 2005, 'p27kip1 deficiency confers susceptibility to gastric carcinogenesis in helicobacter pylori-infected mice', Gastroenterology, vol. 129, no. 5, pp. 1544-1556. https://doi.org/10.1053/j.gastro.2005.07.056
Kuzushita, Noriyoshi ; Rogers, Arlin B. ; Monti, Nola A. ; Whary, Mark T. ; Park, Min J. ; Aswad, Bassam I. ; Shirin, Haim ; Koff, Andrew ; Eguchi, Hidetoshi ; Moss, Steven F. / p27kip1 deficiency confers susceptibility to gastric carcinogenesis in helicobacter pylori-infected mice. In: Gastroenterology. 2005 ; Vol. 129, No. 5. pp. 1544-1556.
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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.",
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AU - Kuzushita, Noriyoshi

AU - Rogers, Arlin B.

AU - Monti, Nola A.

AU - Whary, Mark T.

AU - Park, Min J.

AU - Aswad, Bassam I.

AU - Shirin, Haim

AU - Koff, Andrew

AU - Eguchi, Hidetoshi

AU - Moss, Steven F.

PY - 2005/1/1

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N2 - 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.

AB - 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.

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