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Abstract：
BACKGROUND: Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer.
METHODS: A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays.
RESULTS: H. pylori can colonize the host\'s stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression.
CONCLUSIONS: H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.
METHODS: A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays.
RESULTS: H. pylori can colonize the host\'s stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression.
CONCLUSIONS: H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.
摘要：
背景：幽门螺杆菌(H.pylori）感染在胃癌的发展和发生中至关重要。幽门螺杆菌分泌γ-谷氨酰转移酶（GGT），影响间充质干细胞的能量代谢和组蛋白甲基化。然而,其对人胃上皮细胞的影响尚不清楚。本研究旨在探讨GGT对胃上皮细胞能量代谢和组蛋白甲基化的影响，并确定其在幽门螺杆菌诱导的胃癌发生发展中的作用。
方法：构建GGT基因敲除H.pylori株和小鼠胃癌模型,并加入α-酮戊二酸(α-KG)。使用蛋白质组学研究了潜在的机制，免疫组织化学，西方印迹,和其他实验测定。
结果：H.幽门螺杆菌可以定植宿主的胃并破坏胃上皮。幽门螺杆菌分泌的GGT降低了胃中谷氨酰胺的浓度，增加了H3K9me3和H3K27me3的表达，促进胃上皮细胞的增殖和迁移。此外,α-KG逆转了这种效应。GGT增加了裸鼠的致瘤能力。GGT,由幽门螺杆菌分泌，促进核糖体蛋白L15（RPL15）的表达，而GGT敲除和补充α-KG和三甲基化抑制剂降低了RPL15表达和Wnt信号通路表达。
结论：H.幽门螺杆菌分泌的GGT降低了胃上皮细胞中谷氨酰胺和α-KG的表达，增加组蛋白H3K9me3和H3K27me3的表达，并通过RPL15的表达激活Wnt信号通路，改变胃上皮的生物学特性,促进胃癌的发生。能量代谢改变和组蛋白甲基化是参与这一过程的重要因素。
方法：构建GGT基因敲除H.pylori株和小鼠胃癌模型,并加入α-酮戊二酸(α-KG)。使用蛋白质组学研究了潜在的机制，免疫组织化学，西方印迹,和其他实验测定。
结果：H.幽门螺杆菌可以定植宿主的胃并破坏胃上皮。幽门螺杆菌分泌的GGT降低了胃中谷氨酰胺的浓度，增加了H3K9me3和H3K27me3的表达，促进胃上皮细胞的增殖和迁移。此外,α-KG逆转了这种效应。GGT增加了裸鼠的致瘤能力。GGT,由幽门螺杆菌分泌，促进核糖体蛋白L15（RPL15）的表达，而GGT敲除和补充α-KG和三甲基化抑制剂降低了RPL15表达和Wnt信号通路表达。
结论：H.幽门螺杆菌分泌的GGT降低了胃上皮细胞中谷氨酰胺和α-KG的表达，增加组蛋白H3K9me3和H3K27me3的表达，并通过RPL15的表达激活Wnt信号通路，改变胃上皮的生物学特性,促进胃癌的发生。能量代谢改变和组蛋白甲基化是参与这一过程的重要因素。
