Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Commun Signal. 2024 Aug 15;22(1):402. doi: 10.1186/s12964-024-01780-x.
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.
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.
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.
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.
幽门螺杆菌（H. pylori）感染在胃癌的发生发展中起着关键作用。H. pylori 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及其在 H. pylori 诱导胃癌发生发展中的作用。
构建了 GGT 敲除 H. pylori 菌株和小鼠胃癌模型，并添加了α-酮戊二酸（α-KG）。采用蛋白质组学、免疫组织化学、Western blot 等实验方法研究其作用机制。
H. pylori 可定植于宿主胃内并破坏胃上皮细胞。H. pylori 分泌的 GGT 降低胃内谷氨酰胺浓度，增加 H3K9me3 和 H3K27me3 的表达，促进胃上皮细胞的增殖和迁移。此外，α-KG 可逆转这种作用。GGT 增加了裸鼠的致瘤能力。H. pylori 分泌的 GGT 促进核糖体蛋白 L15（RPL15）的表达，而 GGT 敲除和补充α-KG 及三甲基化抑制剂可降低 RPL15 的表达及 Wnt 信号通路的表达。
H. pylori 分泌的 GGT 降低了胃上皮细胞中谷氨酰胺和α-KG 的表达，增加了组蛋白 H3K9me3 和 H3K27me3 的表达，通过 RPL15 的表达激活了 Wnt 信号通路，最终改变了胃上皮细胞的生物学特性，促进了胃癌的发生。能量代谢改变和组蛋白过度甲基化是该过程的重要因素。
