Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
Department of Cellular Pathology, Nottingham University Hospitals NHS Trust, Queen's Medical Centre Campus, Nottingham, UK.
J Pathol. 2022 Oct;258(2):199-209. doi: 10.1002/path.5990. Epub 2022 Aug 18.
High-level expression of decay-accelerating factor, CD55, has previously been found in human gastric cancer (GC) and intestinal metaplasia (IM) tissues. Therapeutic effects of CD55 inhibition in cancer have been reported. However, the role of Helicobacter pylori infection and virulence factors in the induction of CD55 and its association with histological changes of the human gastric mucosa remain incompletely understood. We hypothesised that CD55 would be increased during infection with more virulent strains of H. pylori, and with more marked gastric mucosal pathology. RT-qPCR and immunohistochemical analyses of gastric biopsy samples from 42 H. pylori-infected and 42 uninfected patients revealed that CD55 mRNA and protein were significantly higher in the gastric antrum of H. pylori-infected patients, and this was associated with the presence of IM, but not atrophy, or inflammation. Increased gastric CD55 and IM were both linked with colonisation by vacA i1-type strains independently of cagA status, and in vitro studies using isogenic mutants of vacA confirmed the ability of VacA to induce CD55 and sCD55 in gastric epithelial cell lines. siRNA experiments to investigate the function of H. pylori-induced CD55 showed that CD55 knockdown in gastric epithelial cells partially reduced IL-8 secretion in response to H. pylori, but this was not due to modulation of bacterial adhesion or cytotoxicity. Finally, plasma samples taken from the same patients were analysed for the soluble form of CD55 (sCD55) by ELISA. sCD55 levels were not influenced by IM and did not correlate with gastric CD55 mRNA levels. These results suggest a new link between active vacA i1-type H. pylori, IM, and CD55, and identify CD55 as a molecule of potential interest in the management of IM as well as GC treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
先前已发现高表达衰变加速因子（Decay-accelerating factor，CD55）与人类胃癌（GC）和肠上皮化生（IM）组织相关。已有报道称，CD55 抑制疗法对癌症具有治疗效果。然而，幽门螺杆菌（Helicobacter pylori）感染及其毒力因子在诱导 CD55 中的作用，以及与人类胃黏膜组织学变化的关联尚不完全清楚。我们假设，在感染毒力更强的 H. pylori 菌株时，CD55 的表达会增加，同时胃黏膜病理变化也会更加显著。我们对 42 例 H. pylori 感染患者和 42 例未感染患者的胃活检样本进行了 RT-qPCR 和免疫组织化学分析，结果显示，在 H. pylori 感染患者的胃窦部，CD55 mRNA 和蛋白的表达显著升高，且与 IM 的存在相关，而与萎缩或炎症无关。增加的胃 CD55 和 IM 均与 vacA i1 型菌株定植相关，而与 cagA 状态无关，使用 vacA 同基因突变株的体外研究证实了 VacA 诱导胃上皮细胞系中 CD55 和 sCD55 的能力。通过 siRNA 实验研究 H. pylori 诱导的 CD55 的功能，结果显示，胃上皮细胞中 CD55 的敲低部分减少了对 H. pylori 的 IL-8 分泌，但这不是由于调节细菌黏附或细胞毒性所致。最后，通过 ELISA 分析从同一患者采集的血浆样本，检测可溶性 CD55（sCD55）的水平。IM 对 sCD55 水平没有影响，且与胃 CD55 mRNA 水平不相关。这些结果表明，活性 vacA i1 型 H. pylori、IM 和 CD55 之间存在新的联系，并确定 CD55 是 IM 以及 GC 治疗中具有潜在应用价值的一个分子。
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