Kubo Shuichi, Ninomiya Ryo, Kajiwara Tooru, Tokunaga Akinori, Matsuda Seiji, Murakami Kazunari, Yamaoka Yoshio, Aigaki Toshiro, Hamada Fumihiko
Department of Anatomy, Faculty of Medicine, Oita University, Yufu, Oita, 879-5593, Japan.
Division of Laboratory Animal Resources, Life Science Research Laboratory, University of Fukui, Eiheiji, Fukui, 910-1193, Japan.
Biochem Biophys Res Commun. 2025 Mar 1;750:151421. doi: 10.1016/j.bbrc.2025.151421. Epub 2025 Jan 29.
Helicobacter pylori (H. pylori) infection is one of the major risk factors of stomach cancer. Strains carrying the oncogenic cytotoxin CagA (cytotoxin-associated gene A) induce epithelial-mesenchymal transition (EMT) and contribute to tumor progression and metastasis. However, the mechanism in which CagA induces EMT has not been defined. In this study, using genetic methods in Drosophila, we identified Semaphorin 5A (SEMA5A) as a new target for CagA. We showed that infection with CagA-positive H. pylori downregulated the expression level of SEMA5A to induce expression of EMT-driving transcription factor Snail and mesenchymal marker N-cadherin, and promote invasive behavior in gastric epithelial cells. Furthermore, we demonstrated that transient over-expression of SEMA5A in H. pylori-infected cells inhibited CagA-mediated gain of mesenchymal phenotype. These results suggest that SEMA5A could be a key mediator of EMT and gastric carcinogenesis caused by CagA-positive H. pylori infection.
幽门螺杆菌（H. pylori）感染是胃癌的主要危险因素之一。携带致癌细胞毒素CagA（细胞毒素相关基因A）的菌株可诱导上皮-间质转化（EMT），并促进肿瘤进展和转移。然而，CagA诱导EMT的机制尚未明确。在本研究中，我们利用果蝇的遗传学方法，确定了信号素5A（SEMA5A）是CagA的一个新靶点。我们发现，感染CagA阳性的幽门螺杆菌会下调SEMA5A的表达水平，从而诱导EMT驱动转录因子Snail和间充质标志物N-钙黏蛋白的表达，并促进胃上皮细胞的侵袭行为。此外，我们证明在幽门螺杆菌感染的细胞中瞬时过表达SEMA5A可抑制CagA介导的间充质表型获得。这些结果表明，SEMA5A可能是CagA阳性幽门螺杆菌感染导致EMT和胃癌发生的关键介质。
