幽门螺杆菌诱导 GBA1 去甲基化,抑制胃癌中的铁卟啉酶活性

IF 3.5 2区 生物学 Q3 CELL BIOLOGY
Chenjie Shen, Huan Liu, Yuhan Chen, Mengpei Liu, Qian Wang, Jiaqi Liu, Jingjing Liu
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引用次数: 0

摘要

这项研究调查了胃癌的潜在治疗靶点,重点是与铁蛋白沉积有关的基因。众所周知,胃癌的生存率较低,因此需要新的治疗策略。本研究采用孟德尔随机化方法鉴定胃癌中的铁变态相关基因和甲基化位点,利用单细胞数据集和TCGA-STAD数据库研究幽门螺杆菌感染、GBA1基因表达和启动子甲基化之间的相关性。我们使用幽门螺杆菌感染的胃癌细胞模型,并使用新一代测序技术监测感染前后的甲基化变化。通过 qRT-PCR 和 Western 印迹评估了感染前后 GBA1 的表达水平。在敲除 GBA1 基因后,使用 CCK-8 和 EdU 检测法分析了幽门螺杆菌对 GC 细胞增殖的影响。利用FerrOrange、GSH、MDA和C11-BODIPY检测法评估了幽门螺旋杆菌感染与铁中毒之间的关系,包括GBA1基因敲除后的可逆性。质谱法测量了幽门螺旋杆菌和 GBA1 基因敲除对脂质代谢的影响。为了证实这些发现,还建立了一个体内皮下肿瘤模型。孟德尔随机分析表明,GBA1的高表达及其启动子甲基化水平的降低是胃癌的危险因素。单细胞测序和TCGA-STAD数据集显示,幽门螺杆菌感染与GBA1表达呈正相关,同时GBA1启动子甲基化与GBA1表达呈负相关。在胃癌细胞系中,幽门螺旋杆菌感染会增强 GBA1 的表达,降低其启动子的甲基化水平。此外,幽门螺旋杆菌还能促进胃癌细胞的增殖,而通过敲除 GBA1 则可减轻这种影响。幽门螺杆菌感染还降低了 GC 细胞的脂质过氧化反应,增加了谷胱甘肽水平,阻碍了铁变态反应;然而,在敲除 GBA1 后,这些影响都被逆转了。在 GC 细胞系中检测到了 I 诱导的鞘脂代谢变化。使用皮下肿瘤模型进行的体内实验表明,幽门螺杆菌感染促进了 GC 细胞的肿瘤发生。我们的研究表明,幽门螺旋杆菌感染会引发 GBA1 的去甲基化和上调,进而抑制胃癌细胞的铁凋亡。这些研究结果表明,靶向 GBA1 通路可为治疗胃癌提供一种新的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Helicobacter pylori induces GBA1 demethylation to inhibit ferroptosis in gastric cancer

Helicobacter pylori induces GBA1 demethylation to inhibit ferroptosis in gastric cancer

This research investigates potential therapeutic targets for gastric cancer, focusing on ferroptosis-related genes. Gastric cancer is known for its lower survival rates, necessitating new treatment strategies. This study employed Mendelian randomization to identify ferroptosis-related genes and methylation sites in gastric cancer, examining correlations between Helicobacter pylori infection, GBA1 gene expression, and promoter methylation with single-cell datasets and the TCGA-STAD database. We used Helicobacter pylori-infected gastric cancer cell models and used next-generation sequencing to monitor methylation changes pre- and post-infection. GBA1 expression levels were assessed via qRT-PCR and Western blot both before and after infection. The effect of Helicobacter pylori on GC cell proliferation was analyzed using CCK-8 and EdU assays after knocking down the GBA1 gene. The association between Helicobacter pylori infection and ferroptosis, including its reversibility after GBA1 knockdown, was evaluated using FerrOrange, GSH, MDA, and C11-BODIPY assays. Mass spectrometry measured the impact of Helicobacter pylori and GBA1 knockdown on lipid metabolism. An in vivo subcutaneous tumor-bearing model was also established to confirm these findings. Mendelian randomization analysis revealed that high GBA1 expression and reduced methylation levels of its promoter are risk factors for gastric cancer. Single-cell sequencing and TCGA-STAD datasets indicated a positive correlation between Helicobacter pylori infection and GBA1 expression, with a concurrent negative correlation between GBA1 promoter methylation and GBA1 expression. In gastric cancer cell lines, Helicobacter pylori infection was observed to enhance GBA1 expression and decrease methylation levels at its promoter. Additionally, Helicobacter pylori promoted GC cell proliferation, an effect mitigated by knocking down GBA1. Infection also reduced lipid peroxidation, increased glutathione levels, and impeded ferroptosis in GC cells; however, these effects were reversed following GBA1 knockdown. Changes in sphingolipid metabolism induced by I were detected in GC cell lines. In vivo experiments using a subcutaneous tumor-bearing model demonstrated that Helicobacter pylori infection fosters tumorigenesis in GC cells. Our study demonstrates that Helicobacter pylori infection triggers demethylation and upregulation of GBA1, subsequently inhibiting ferroptosis in gastric cancer cells. These findings suggest that targeting the GBA1 pathway may offer a novel therapeutic approach for managing gastric cancer.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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