Elucidating the mechanism of Hit-and-Run carcinogenesis by H. pylori CagA through a CagA-inducible mice model

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In the study, a new inducible mouse model of H. pylori CagA, Gt(ROSA)26Sor(CAG-LSL-cagA) (CAG-LSL-cagA), was established. Using this in vivo model, we demonstrated that acute ubiquitous expression of CagA induces embryonic lethality in mice due to aberrant activation of Shp2.In adult mice, acute ubiquitous expression of CagA disrupted the gastric epithelium, resulting in the loss of mucous neck cells and parietal cells, drastically reducing mucin and acid secretion, respectively. DNA damage (p-γH2AX) was observed in the gastric epithelium in a CagA-dependent manner which perturbed gastric turnover by eliciting DNA damage-induced p21 accumulation in stem cell populations. Prolonged gastric-specific expression of CagA resulted in the development of gastric hyperplasia and adenocarcinoma, where p53 expression was attenuated in the tumor regions.Subsequent analysis using ex vivo mice gastric organoid models demonstrated that while acute CagA expression inhibits organoid maintenance, knockdown of p53 rescues gastric organoids from CagA-induced growth inhibition.Using both in vivo and ex vivo systems, the author demonstrated that CagA induces DNA damage to the gastric epithelium, including the stem cell population, resulting in accumulation of mutations and mutations of key tumor suppressors such as p53, an essential early step in CagA-induced gastric carcinogenesis.Overall, this study utilized a variety of experimental procedures and design which resulted in exceptional progress in CagA-dependent carcinogenesis, which was more than expected at the start of this study.