Department of Medical Oncology, Affiliated Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.
Department of Respiratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
Oxid Med Cell Longev. 2020 Mar 6;2020:7370157. doi: 10.1155/2020/7370157. eCollection 2020.
The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation and , decreased the IC values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.
本研究旨在探讨谷胱甘肽过氧化物酶家族（GPXs，GSH-Px）成员 GPX2 在肺腺癌（LUAD）顺铂（DDP）耐药中的作用。通过 RNA 测序发现，与亲本 A549 细胞系相比，DDP 耐药 A549/DDP 细胞系中 GPX2 是上调最显著的基因。在 A549/DDP 细胞中敲低 GPX2 表达可抑制细胞增殖和克隆形成，降低 DDP 的 IC 值，诱导细胞凋亡，抑制 GSH-Px 和超氧化物歧化酶（SOD）活性，抑制 ATP 产生和葡萄糖摄取，增加丙二醛（MDA）和活性氧（ROS）的产生；而在 A549 细胞中过表达 GPX2 则产生相反的效果。通过基因集富集分析（GSEA）发现，GPX2 可能通过调节药物代谢、细胞周期、DNA 修复和能量代谢以及 ABCB6（一种糖酵解的标志性基因）的表达，从而参与 DDP 耐药。此外，免疫组织化学显示，在 58.6%（89/152）的 LUAD 病例中 GPX2 表达上调，且 GPX2 表达升高与 ABCB6 高表达、18F-氟脱氧葡萄糖（18F-FDG）摄取高以及本队列不良无病生存（DFS）相关。癌症基因组图谱（TCGA）数据也表明，与正常肺组织相比，GPX2 在 LUAD 中的表达更高，且 GPX2 和 ABCB6 的 mRNA 表达水平呈正相关。综上所述，本研究表明 GPX2 在 LUAD 中作为癌基因发挥作用，并通过调节氧化应激和能量代谢促进 DDP 耐药。
