Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(12):2597-2604; doi:10.1093/carcin/bgm150
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Protective role of 17β-estradiol against the development of Helicobacter pylori-induced gastric cancer in INS-GAS mice
1 Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16-825C, Cambridge, MA 02139, USA
2 Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA
3 Present address: 2nd Department of Internal Medicine, Faculty of Medical Science, Fukui University, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
* To whom correspondence should be addressed. Tel: +1 617 253 1735; Fax: +1 617 252 1877; Email: jgfox{at}mit.edu
The incidence of gastric cancer is higher in men than women. Epidemiological studies suggest that female hormones reduce gastric cancer risk. We examined the effect of ovarian-dependent female hormones on Helicobacter pylori-induced gastric cancer in hypergastrinemic INS-GAS mice. Male and female sexually intact or ovariectomized (OVX) mice were inoculated with H.pylori SS1 or vehicle-only at 10 weeks of age, and tissues were evaluated at 16 or 28 weeks post-infection (WPI). A subset of OVX females were supplemented with 17β-estradiol (E2), beginning at 16 WPI. Stomachs were evaluated by histopathology, Ki-67 proliferation index, H.pylori quantitative culture and quantitative polymerase chain reaction for messenger RNA expression of inducible nitric oxide synthase (iNOS) and inflammatory cytokines. Infected OVX females developed significantly more severe gastritis (P < 0.05) than infected intact females at both time points. E2 treatment in infected OVX females attenuated the severity of gastritis. Gastrointestinal intraepithelial neoplasia (GIN) developed in 42% of infected males and 10% of infected OVX females by 28 WPI, whereas infected intact females and E2-treated OVX females did not develop GIN. Infected OVX females showed significantly increased iNOS expression and epithelial cell proliferation when compared with intact, infected females. Likewise, interferon-gamma, tumor necrosis factor-alpha and interleukin-1β (IL-1β) expression in infected OVX females were significantly increased at 28 WPI when compared with intact counterparts. E2 treatment in infected OVX females significantly decreased IL-1β expression, increased IL-10 expression and reduced epithelial cell proliferation. These results demonstrate a protective effect of E2 in H.pylori-induced gastric cancer in a mouse model.
Abbreviations: ERβ, estrogen receptor β; E2, 17β-estradiol; GIN, gastrointestinal intraepithelial neoplasia; IFN-
, interferon-gamma; IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase; LI, labeling index; mRNA, messenger RNA; OVX, ovariectomized; TNF-
, tumor necrosis factor-alpha; WPI, weeks post-infection
Received April 2, 2007; revised June 4, 2007; accepted June 14, 2007.
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