Dataset Information

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma.

ABSTRACT: 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 in vitro and in vivo, decreased the IC50 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.

SUBMITTER: Du H

PROVIDER: S-EPMC7079220 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma.

Du He H Chen Bi B Jiao Nan-Lin NL Liu Yan-Hua YH Sun San-Yuan SY Zhang You-Wei YW

Oxidative medicine and cellular longevity 20200306

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 in vitro and in vivo, decreased the IC50 values of DDP, ...[more]

PMID: 32215178

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Project description:The mechanism of RP11-838N2.3 promoting cisplatin resistance in lung adenocarcinoma (LAD) was unclear. The RP11-838N2.3 expression level in cells and LAD tissues was detected by qPCR. We constructed lentivirus-mediated GV303 overexpression and GV248 shRNA vector targeting RP11-838N2.3, then infected A549 and A549/DDP cell and furtherly analyzed cell biology. High-throughput gene chip analysis showed that RP11-838N2.3 was significantly upregulated in A549/DDP (change?fold = 66.056595). The qPCR results showed that the expression level of RP11-838N2.3 in A549/DDP cell was significantly higher than that in A549 cells (P < 0.05), and the expression level of RP11-838N2.3 in LAD tissues was also significantly higher than that in adjacent tissues (P < 0.05). The expression level of RP11-838N2.3 in cisplatin-insensitive LAD tissues was also significantly higher than that in cisplatin-sensitive LAD tissues (P < 0.05). Survival analysis showed that OS (overall survival) and DFS (progression-free survival) of high RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group were lower (P < 0.001 and P < 0.001) than those of low RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group. CCK8 showed that the OD450 value of RP11-838N2.3 overexpression increased significantly at 24?h, 48?h, and 72?h after transfection, while the knockdown of RP11-838N2.3 caused OD450 value at 24?h, 48?h, and 72?h after transfection significantly reduced, under the action of cisplatin that had the same trend (P < 0.05). The cell migration showed that the RP11-838N2.3 overexpression increased significantly migration activity and RP11-838N2.3 knockdown inhibited migration activity at 24?h, 48?h, and 72?h after transfection. The same trend was also observed under the action of cisplatin (P < 0.05). The cell invasion showed that the invasion rate of RP11-838N2.3 overexpression increased significantly, while the invasion rate of RP11-838N2.3 knockdown decreased significantly, and the same trend was observed under the action of cisplatin (P < 0.05). Apoptosis results showed that the apoptosis rate of RP11-838N2.3 overexpressed cells decreased significantly and the apoptosis rate of RP11-838N2.3 knockdown cells increased significantly, and the same trend was also observed under the action of cisplatin (P < 0.05). However, the results of cell cycle showed that there was no significant difference in the proportion of cells in each phase of the cell cycle after RP11-838N2.3 overexpression or knockdown (P > 0.05).RP11-838N2.3 was significantly upregulated in cisplatin-resistant cell and tissues of LAD. RP11-838N2.3 could enhance the proliferation, migration, and invasion and inhibit apoptosis of LAD cisplatin-resistant cell. So RP11-838N2.3 could enhance the cisplatin resistance of LAD cells and was a resistant lncRNA molecule.

Project description:Cisplatin (DDP) resistance has become the major obstacle in the therapy of malignant tumors, including lung adenocarcinoma (LAD). Long non-coding RNAs (lncRNAs) were confirmed to be related to DDP-resistance. Studies have shown that RP3-326I13.1 (also known as PINCR) could promote the progression of colorectal cancer, and RP3-326I13.1 knockdown could induce hypersensitivity to chemotherapy drugs. While the function of RP3-326I13.1 in LAD is unclear, therefore, this study aimed to research the biological function and related molecular mechanisms of RP3-326I13.1 in DDP-resistance of LAD. QPCR analysis found that RP3-326I13.1 was highly expressed in A549/DDP cells and LAD tissues. Cytological assays found that RP3-326I13.1 pro-moted the proliferation, migration, invasion, and DDP-resistance of LAD cell lines. Moreover, knock-down of RP3-326I13.1 could induce G1 phase arrest. Nude mouse xenograft assay confirmed that RP3-326I13.1 could promote tumor growth and DDP-resistance in vivo. Mechanically, RNA pull-down and mass spectrometry analysis indicated that heat shock protein HSP 90-beta (HSP90B) could be combined with RP3-326I13.1. HSP90B knockdown inhibited the effect of RP3-326I13.1 on proliferation, invasion, and promoted LAD cell lines apoptosis. Transcriptome sequencing analysis found that MMP13 was the downstream mRNA of RP3-326I13.1. In conclusion, RP3-326I13.1 could promote DDP-resistance of LAD by binding to HSP90B and upregulating human matrix metalloproteinase-13 (MMP-13) and may serve as a therapeutic target, as well as a biomarker for predicting DDP-resistance in LAD.Abbreviations:DDP: Cisplatin; LAD: Lung adenocarcinoma; LncRNAs: Long non-coding RNAs; qPCR: real-time fluorescent quantitative PCR; HSP90B: Heat shock protein HSP 90-beta; RPMI: Roswell Park Memorial Institute; FBS: Fetal bovine serum; CT: computed tomography; MRI: magnetic resonance imaging; RECIST: Response evaluation criteria in solid tumors; NC: Negative control; OE: overexpression; shRNA: short hairpin RNA; siRNA: small interfering RNA; CCK-8: Cell Counting Kit-8; IC50: The half maximal inhibitory concentration; PBS: Phosphate buffer saline; PI: propidium iodide; SDS-PAGE: sodiumdodecylsulfate-polyacrylamide gel electrophoresis; ceRNA: Competing endogenous RNA; HE: hematoxylin-eosin; ns: no significance.

Dataset Information

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma.

Publications

Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma.

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