br cells in H pylori infected gastric mucosa br Increased
cells in H pylori–infected gastric mucosa.
Increased expression of SALL4 and KLF5 induced by ported that H pylori infection and gastric cancer are closely 1154
CagA promotes an intestinal stem/progenitor-like state and related, and that eradication therapy helps to prevent 1155
thereby is implicated in intestinal metaplasia of the gastric metachronous gastric carcinogenesis. However, the annual 1156
mucosa.22 This suggests that acquisition of stem cell prop- incidence of metachronous gastric cancer is up to 2.5%, 1157
erties in gastric epithelial Salvinorin A via CagA-mediated up-regu- indicating that gastric cancer develops even after bacterial 1158
development of gastric cancer. Here, H pylori infection overexpressing cells remaining in the gastric mucosa af- 1160
increased mRNA expression of SALL4 and KLF5 in CAPZA1- ter eradication therapy increase the risk of metachronous 1161
overexpressing cells more than in pCMV6-ctrl–transfected gastric cancer and that reduction of CAPZA1 expression by 1162
cells (Figure 2E). Therefore, H pylori was considered to amelioration of chronic inflammation after eradication 1163
robustly induce stem cell properties in CAPZA1- therapy is important to prevent the development of gastric 1164
overexpressing gastric epithelial cells.
H pylori mainly adheres to mucus pit cells, which are The present study focused on whether CAPZA1- 1166
terminally differentiated cells with a short lifespan, and overexpressing cells are progenitors of CD44v9-positive 1167
Figure 5. (See previous page). The CAPZA1 expression level correlates with the level of oxidative stress injury induced 1170
by H pylori infection in the gastric mucosa. (A) Mongolian gerbils were inoculated with H pylori KS strains (8 108 colony- 1171
Western blot of protein extracts for CAPZA1 was performed. The CAPZA1 signal intensity in each mouse was analyzed using 1173
ImageJ. The data points indicate the CAPZA1 signal intensity in each animal. *P < .05. P values were calculated by the Student
t test. (B) Levels of malondialdehyde and protein carbonylation in gastric tissues of Mongolian gerbils infected with H pylori KS
strains or vehicle were measured. Correlation coefficients between CAPZA1 expression and levels of malondialdehyde and
protein carbonylation were determined by correlation analysis. (C) Immunostaining analysis of CAPZA1 and 8-hydroxy-2’-
deoxyguanosine (8-OHDG) in gastric mucosa of 10 Mongolian gerbils infected with or without H pylori (5 per group). Red 1177
indicates CAPZA1 and green indicates 8-OHDG. Scale bar: 20 mm. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. 1178
Figure 6. Representative immunostaining results for co-localization of CAPZA1 and CD44v9 in gastric mucosa of Mon-golian gerbils infected with H pylori. CD44v9-positive cells were detec-ted in gastric mucosa of 2 of 5 Mongolian gerbils infected with H pylori (no. 3 and 4). Red indicates CAPZA1 and green in-dicates CD44v9. The white box contains CD44v9-positive cells and is enlarged at the bottom of each panel. Scale bar: 20 mm.
cells in H pylori–infected gastric mucosa. CAPZA1-overexpressing cells were detected in both poorly differen-tiated (cases 1, 2, and 3) and well-differentiated (cases 4 and
5) adenocarcinoma, and these cells expressed CD44v9 (Figure 1). Overall, our data show that CD44v9-positive cells
arise from CAPZA1-overexpressing cells in H pylori–infected gastric mucosa. Lee et al34 reported that the appearance of CAPZA1-overexpressing cells is related to well-differentiated tumors, but there is no difference in terms of
intestinal- and diffuse-type adenocarcinomas. In addition, Go et al35 showed that the positive expression rate of CD44v9 is increased significantly in well-differentiated adenocarci-noma. Based on these reports, the positive expression rate of CD44v9 may correlate with the appearance of CAPZA1-overexpressing cells, consistent with our results.
Cancer stem cells, which have similar characteristics to tissue stem/progenitor cells,36 are believed to be key tumor-initiating cells and underlie cancer recurrence.37 We previ-ously reported that the rate of gastric cancer recurrence among patients who have undergone endoscopic treatment for primary early gastric cancer is significantly higher in the
CD44v9-positive cohorts than in the CD44v9-negative co-horts.5 Here, we show that CAPZA1-overexpressing cells are progenitors of CD44v9-positive cells. Thus, the present study provides important insights into the mechanisms underlying gastric carcinogenesis in H pylori–infected gastric mucosa, which can be used to prevent de novo development and metachronous recurrence of gastric cancer.