Glutathione peroxidase 2 overexpression promotes malignant progression and cisplatin resistance of KRAS‑mutated lung cancer cells.

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) aberrations frequently occur in patients with lung cancer. Oncogenic KRAS is characterized by excessive reactive oxygen species (ROS) accumulation, thus, ROS detoxification may contribute to KRAS-driven lung tumorigenesis. In the present study, the influence of glutathione peroxidase 2 (GPX2) on malignant progression and cisplatin resistance of KRAS-driven lung cancer was explored. The RNA sequencing data from TCGA lung cancer samples and GEO database were downloaded and analyzed. The effects of GPX2 on KRAS-driven lung tumorigenesis were evaluated by western blotting, cell viability assay, soft agar assay, Transwell assay, tumor xenograft model, flow cytometry, BrdU incorporation assay, transcriptome RNA sequencing, luciferase reporter assay and RNA immunoprecipitation. In the present study, GPX2 was upregulated in patients with non-small cell lung carcinoma (NSCLC), and positively correlated with poor overall survival. Ectopic GPX2 expression facilitated malignant progression of KRASG12C-transformed BEAS-2B cells. Moreover, GPX2 overexpression promoted growth, migration, invasion, tumor xenograft growth and cisplatin resistance of KRAS-mutated NSCLC cells, while GPX2 knockdown exhibited the opposite effects. GPX2 overexpression reduced ROS accumulation and increased matrix metalloproteinase-1 (MMP1) expression in KRAS-mutated NSCLC cells. In addition, GPX2 was directly targeted by miR-325-3p, while MMP1 knockdown or miR-325-3p overexpression partially abrogated the effects of GPX2 in NSCLC cells. In conclusion, the results indicated that GPX2 facilitated malignant progression and cisplatin resistance of KRAS-driven lung cancer, and inhibition of GPX2 may be a feasible strategy for lung cancer treatment, particularly in patients with active KRAS mutations.