Abstract
Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1−/− mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2−/− mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1−/−, Nfkb2−/− and c-Rel−/− mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1−/− mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1−/− mice than in WT mice. Nfkb1−/− mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1−/− mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1−/− mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1−/− mice to DNA damage.
Highlights
Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice
We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits
Tamoxifen induced gastric corpus pathology is regulated by Nfkb[1]
Summary
Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration This is associated with an exaggerated gastric epithelial DNA damage response. Gastric cancer in humans is strongly associated with gastric colonization with Helicobacter pylori.[1] This leads, in a minority of people, to a preneoplastic cascade of pathology that develops over several decades This cascade is typified by gastric oxyntic gland atrophy, epithelial metaplasia, dysplasia and cancer.[2] These events can be modeled by infecting C57BL/6 mice with the related bacterium Helicobacter felis. In this model, advanced gastric preneoplasia develops over 12 months and, in some hands, malignancies have been reported in animals aged 13–15 months.[3,4]. The alternative (non-canonical) NF-κB signaling pathway is regulated by the kinase NIK and is characterized by transcriptional regulation by dimers of RelB/NF-κB2 (see Merga et al.[5] for a recent review of these pathways)
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