p27kip1 deficiency confers susceptibility to gastric carcinogenesis in Helicobacter pylori-infected mice.
OBJECTIVE
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.
Kuzushita
Noriyoshi
N
Division of Gastroenterology, Department of Medicine, Rhode Island Hospital/Brown University, Providence, Rhode Island 02903, USA.
Rogers
Arlin B
AB
Monti
Nola A
NA
Whary
Mark T
MT
Park
Min J
MJ
Aswad
Bassam I
BI
Shirin
Haim
H
Koff
Andrew
A
Eguchi
Hidetoshi
H
Moss
Steven F
SF
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005755:Gastrins / Q000097:blood; D005756:Gastritis / Q000150:complications / Q000235:genetics / Q000382:microbiology; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D016480:Helicobacter pylori; D006965:Hyperplasia; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology
D005755:Gastrins; D050760:Cyclin-Dependent Kinase Inhibitor p27