Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho Aoba-ku, Sendai, Miyagi, 981-8574, Japan.
Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan.
Dig Dis Sci. 2024 Jan;69(1):95-111. doi: 10.1007/s10620-023-08142-6. Epub 2023 Nov 9.
Recent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease.
We aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development.
To evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis.
In the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-β-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-β-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, β-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with β-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration.
Local exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-β-catenin-signaling in GC.
最近的流行病学研究表明胃癌（GC）与牙周病之间存在相关性。
我们旨在阐明牙龈卟啉单胞菌（Pg.）的脂多糖（一种红色复合体牙周病原体）在 GC 发展中的作用。
为了评估背景黏膜对刺激的屏障功能，我们使用 Ussing 室系统（UCs）应用了来自 76 名 GC 患者的活检样本。K19-Wnt1/C2mE 转基因（Gan）小鼠和人 GC 细胞系±THP1 衍生的巨噬细胞被应用于研究 Pg.脂多糖在炎症相关致癌中的作用。
在 UCs 中，Pg.脂多糖降低了化生和炎症黏膜的阻抗，同时增加了 Toll 样受体（TLR）2、肿瘤坏死因子（TNF）α 和凋亡标志物的 mRNA 表达。在体外，Pg.脂多糖促进了与活性氧（ROS）相关的凋亡，以及在 MKN7 上激活了 TLR2-β-连环蛋白信号通路，同时增加了巨噬细胞的 TNFα 产生。TNFα 单独在 MKN7 上激活了 TLR2-β-连环蛋白信号通路，同时在巨噬细胞中进一步增加了 ROS 和 TNFα。在与经 Pg.脂多糖刺激分离的巨噬细胞共培养下，MKN7 中的β-连环蛋白信号通路被激活，同时上清液 TNFα 浓度增加，将 TNFα 中和抗体添加到上清液中可降低这两种物质。在接受 Pg.脂多糖口服 15 周的 Gan 小鼠中，观察到肿瘤增大，β-连环蛋白信号通路激活，同时 TNFα 增加，巨噬细胞浸润。
局部暴露于 Pg.脂多糖可能会增加癌前胃黏膜上的 ROS，从而诱导凋亡相关的屏障功能障碍，并从激活的巨噬细胞中分泌 TNFα，而 Pg.脂多糖和 TNFα 的刺激都可能在 GC 中激活 TLR2-β-连环蛋白信号通路。
