Development and validation of an oxidative stress‑related prognostic signature in osteosarcoma: A combination of molecular experiments and bioinformatics

Abstract

Osteosarcoma (OS) is one of the most prevalent malignancies with a bad prognosis. Oxidative stress is closely associated with various type of cancer. The present study aimed to establish an oxidative stress-related gene prognostic signature. Supported by The Cancer Genome Atlas and Gene Expression Omnibus, the least absolute shrinkage and selection operator regression, Cox regression, receiver operating characteristic curves and Kaplan-Meier survival analysis were used to construct and validate a prognostic signature and the derived risk score. Tumor microenvironment scores and immune infiltration levels in OS were calculated. Correlation between these parameters and risk score was analyzed. In addition, single analysis of each hub gene was performed. Finally, a series of molecular experiments was used to detect the role of MAP3K5 (one of the hub genes) in OS. A total of five genes most associated with OS prognosis were identified as independent predictors, namely catalase (CAT), mitogen-activated protein kinase 1 (MAPK1), glucose-6-phosphate dehydrogenase (G6PD), mitogen-activated protein kinase kinase kinase 5 (MAP3K5) and C-C motif chemokine ligand 2 (CCL2). Based on the signature, higher risk score indicated poorer prognosis. Nomogram performed well and reliably predicted 3-and 5-year survival rate in OS. Patients with increasing risk scores had higher tumor purity and lower immune infiltration levels. Compared with an osteoblast cell line, the expression of CAT, CCL2, MAPK1 and G6PD was upregulated and MAP3K5 was downregulated. MAP3K5 inhibited cellular proliferation and motility, promoted cellular apoptosis and induced reactive oxygen species generation. Overall, the signature could effectively predict the prognosis of patients with OS and were expected to be potential biomarkers. And it provided new ideas for understanding the interactions between oxidative stress and OS.

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma

“…G6PD-deficient cells exhibit higher levels of the lipid peroxidation product MDA when exposed to oxidizing agents [147]. OS cells also show increased levels of G6PD [148]. NADP + is required for the enzymatic activity of G6PD, whereas NADPH downregulates it.…”