Celecoxib inhibits Cdx2 expression and prevents gastric cancer in Helicobacter pylori-infected Mongolian gerbils.
OBJECTIVE
The aim of this study was to see whether administration of celecoxib, a selective COX-2 inhibitor, prior to the appearance of intestinal metaplasia could prevent the development of gastric cancer in Helicobacter pylori-infected Mongolian gerbils.


METHODS
Fifty-two Mongolian gerbils were divided into 3 groups and given 5 biweekly doses of N-methyl-N-nitrosourea (MNU; 30 ppm). At week 12, group 2 (n = 20) and group 3 (n = 22) gerbils were then given an injection of H. pylori, while group 1 controls (n = 10) received Brucella broth alone. In addition, 7 weeks after H. pylori inoculation, at week 19, group 3 gerbils also received a 36-week administration course of celecoxib (1,500 ppm) in their diet. The incidence of gastric adenocarcinoma was determined at week 54 by histological analysis. COX-2 and Cdx2 protein expression and COX activity were evaluated for each group. The extent of intestinal metaplasia, Cdx2 and MUC2 expression, and the apoptotic index were evaluated semi-quantitatively by immunohistochemistry.


RESULTS
The incidence of gastric adenocarcinoma was: group 1, 0% (0/10); group 2, 65% (13/20), and group 3, 23% (5/22; p < 0.05). Continuous celecoxib administration significantly reduced COX activity and COX-2 protein expression, Cdx2 and MUC2 protein immunoreactivity, and the extent of Alcian blue periodic acid-Schiff-positive intestinal metaplasia in H. pylori-infected gerbils. Celecoxib also induced apoptosis in these gerbils. Significant inhibition of Cdx2 expression in group 3 gerbils was also shown by Western blot analysis.


CONCLUSIONS
Prior to the first appearance of intestinal metaplasia, timely administration of celecoxib prevents gastric cancer occurrence by disrupting the progression of intestinal metaplasia into gastric carcinoma through its inhibition of Cdx2 expression in MNU-pretreated H. pylori-infected Mongolian gerbils.
Futagami
Seiji
S
Department of Medicine, Division of Gastroenterology, Nippon Medical School, Tokyo, Japan. seiji-f@nms.ac.jp
Suzuki
Kenji
K
Hiratsuka
Tetsuro
T
Shindo
Tomotaka
T
Hamamoto
Tatsuhiko
T
Tatsuguchi
Atsushi
A
Ueki
Nobue
N
Shinji
Yoko
Y
Kusunoki
Masanori
M
Wada
Ken
K
Miyake
Kazumasa
K
Gudis
Katya
K
Tsukui
Taku
T
Sakamoto
Choitsu
C
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D000071616:CDX2 Transcription Factor; D000068579:Celecoxib; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000473:pathology*; D016480:Helicobacter pylori / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D011230:Precancerous Conditions / Q000473:pathology*; D011336:Probability; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*
D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib