Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
BMC Cancer. 2022 Aug 12;22(1):881. doi: 10.1186/s12885-022-09986-3.
Glutathione Peroxidase 4 (GPX4) is a key protein that inhibits ferroptosis. However, its biological regulation and mechanism in endometrial cancer (EC) have not been reported in detail.
The expression of GPX4 in EC tissues was determined by TCGA databases, qRT-PCR, Western blot, and immunohistochemistry (IHC). The effects of GPX4 on EC cell proliferation, migration, apoptosis, and tumorigenesis were studied in vivo and in vitro. In addition, ETS Transcription Factor ELK1 (ELK1) was identified by bioinformatics methods, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP). Pearson correlation analysis was used to evaluate the association between ELK1 and GPX4 expression.
The expression of GPX4 was significantly up-regulated in EC tissues and cell lines. Silencing GPX4 significantly inhibited the proliferation, migration ability, induced apoptosis, and arrested the cell cycle of Ishikawa and KLE cells. Knockdown of GPX4 accumulated intracellular ferrous iron and ROS, disrupted MMP, and increased MDA levels. The xenograft tumor model also showed that GPX4 knockdown markedly reduced tumor growth in mice. Mechanically, ELK1 could bind to the promoter of GPX4 to promote its transcription. In addition, the expression of ELK1 in EC was positively correlated with GPX4. Rescue experiments confirmed that GPX4 knockdown could reverse the strengthens of cell proliferation and migration ability and the lower level of Fe and MDA caused by upregulating ELK1.
The results of the present study suggest that ELK1 / GPX4 axis plays an important role in the progress of EC by promoting the malignant biological behavior and inducing ferroptosis of EC cells, which provides evidence for investigating the potential therapeutic strategies of endometrial cancer.
谷胱甘肽过氧化物酶 4（GPX4）是一种抑制铁死亡的关键蛋白。然而，其在子宫内膜癌（EC）中的生物学调控及其机制尚未详细报道。
通过 TCGA 数据库、qRT-PCR、Western blot 和免疫组织化学（IHC）检测 EC 组织中 GPX4 的表达。在体内和体外研究 GPX4 对 EC 细胞增殖、迁移、凋亡和肿瘤发生的影响。此外，通过生物信息学方法、双荧光素酶报告基因检测和染色质免疫沉淀（ChIP）鉴定 ETS 转录因子 Elk1（ELK1）。采用 Pearson 相关分析评估 ELK1 与 GPX4 表达的相关性。
GPX4 在 EC 组织和细胞系中表达明显上调。沉默 GPX4 可显著抑制 Ishikawa 和 KLE 细胞的增殖、迁移能力，诱导凋亡，阻滞细胞周期。敲低 GPX4 会导致细胞内亚铁离子和 ROS 积累，破坏 MMP，并增加 MDA 水平。异种移植肿瘤模型也表明，敲低 GPX4 可显著减少小鼠肿瘤生长。在机制上，ELK1 可与 GPX4 启动子结合，促进其转录。此外，EC 中 ELK1 的表达与 GPX4 呈正相关。挽救实验证实，上调 ELK1 引起的细胞增殖和迁移能力增强以及 Fe 和 MDA 水平降低可被 GPX4 敲低所逆转。
本研究结果表明，ELK1/GPX4 轴通过促进 EC 细胞的恶性生物学行为和诱导铁死亡，在 EC 的进展中发挥重要作用，为研究子宫内膜癌的潜在治疗策略提供了依据。
