GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1.
GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1.
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DOI：
10.1186/s12885-022-09986-3
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发表时间：
2022-08-12
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
谷胱甘肽过氧化物酶4（GPX 4）是抑制铁凋亡的关键蛋白。然而，其在子宫内膜癌（EC）中的生物学调控和机制尚未有详细报道。通过TCGA数据库、qRT-PCR、Western blot和免疫组织化学（IHC）测定EC组织中GPX 4的表达。在体内和体外研究GPX 4对EC细胞增殖、迁移、凋亡和肿瘤发生的影响。此外，ETS转录因子ELK 1（ELK 1）的生物信息学方法，双荧光素酶报告分析，染色质免疫沉淀（ChIP）进行了鉴定。采用Pearson相关分析评价ELK 1和GPX 4表达之间的相关性。GPX 4在EC组织和细胞系中表达显著上调。GPX 4基因沉默可显著抑制石川细胞和KLE细胞的增殖、迁移能力，诱导细胞凋亡，并使细胞周期阻滞。GPX 4的敲低积累细胞内亚铁和ROS，破坏MMP，并增加MDA水平。异种移植肿瘤模型还表明，GPX 4敲除显着减少了小鼠的肿瘤生长。ELK 1可与GPX 4的启动子结合，促进GPX 4的转录。ELK 1在EC中的表达与GPX 4呈正相关。拯救实验证实GPX 4基因敲减可逆转ELK 1上调所导致的细胞增殖和迁移能力增强以及Fe 2+和MDA水平降低。本研究结果提示，ELK 1/GPX 4轴通过促进EC细胞的恶性生物学行为和诱导EC细胞的铁凋亡，在EC的发生发展中起重要作用，为研究子宫内膜癌的潜在治疗策略提供了依据。在线版本包含补充材料，可通过10.1186/s12885-022-09986-3获得。
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 Fe2+ 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. The online version contains supplementary material available at 10.1186/s12885-022-09986-3.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.2
作者：
López-Janeiro Á;Ruz-Caracuel I;Ramón-Patino JL;De Los Ríos V;Villalba Esparza M;Berjón A;Yébenes L;Hernández A;Masetto I;Kadioglu E;Goubert V;Heredia-Soto V;Barderas R;Casal JI;de Andrea CE;Redondo A;Mendiola M;Peláez-García A;Hardisson D
通讯作者：
Hardisson D
DOI：
10.18632/aging.203172
发表时间：
2021-06-21
期刊：
Aging
影响因子：
--
作者：
Chen W;Fu J;Chen Y;Li Y;Ning L;Huang D;Yan S;Zhang Q
通讯作者：
Zhang Q
影响因子：
5
作者：
通讯作者：
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c-KIT-ERK1/2信号激活ELK1并上调癌胚抗原表达促进结直肠癌进展
影响因子：
5.7
作者：
Ma J;Liu X;Chen H;Abbas MK;Yang L;Sun H;Sun T;Wu B;Yang S;Zhou D
通讯作者：
Zhou D