Ji Hai-Zhou, Chen Li, Ren Mi, Li Sang, Liu Tong-Yu, Chen Hong-Ju, Yu Hui-Hui, Sun Yang
Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
Department of Oncological Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
Pharmaceuticals (Basel). 2023 Aug 25;16(9):1210. doi: 10.3390/ph16091210.
CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-β1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of and . These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate and expression, protecting endothelial cells from ferroptosis.
CXCL8 - CXCR1/CXCR2信号通路可能在卵巢肿瘤微环境中的不同细胞类型之间形成复杂的串扰，从而调节不同细胞的行为。本研究旨在探究CXCL8在卵巢肿瘤微环境中的表达模式及其对内皮 - 间充质转化（EndMT）和内皮细胞铁死亡的影响。使用人单核细胞系THP - 1和人脐静脉内皮细胞系PUMC - HUVEC - T1进行体外研究。使用厄拉司丁诱导铁死亡。结果显示，肿瘤相关巨噬细胞是肿瘤微环境中CXCL8的主要来源。CXCL8处理通过内皮细胞中的CXCR2促进NF - κB p65的核转位和p65磷酸化，提示NF - κB信号激活。通过NF - κB信号通路，CXCL8增强了TGF - β1诱导的PUMC - HUVEC - T1细胞的EndMT，并提高了它们的 和 的表达。在CXCR2敲低或SB225002处理的组中，这些趋势显著减弱。TPCA - 1逆转了CXCL8诱导的SLC7A11和GPX4上调。CXCL8保护内皮细胞免受厄拉司丁诱导的铁死亡。然而，当 被敲低时，这些保护作用在很大程度上被消除。总之，CXCL8可以以CXCR2依赖的方式激活内皮细胞中的NF - κB信号通路。CXCL8 - CXCR2/NF - κB轴可以增强EndMT并激活 和 的表达，保护内皮细胞免受铁死亡。
