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

Xie,Bin; Tan,Shiyong; Li,Chao; Liang,Junyang

doi:10.3892/ol.2023.13865

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

Authors:
- Bin Xie
- Shiyong Tan
- Chao Li
- Junyang Liang
View Affiliations

Affiliations: Second Department of Spinal Surgery, Weihaiwei People's Hospital, Weihai, Shandong 264200, P.R. China
Published online on: May 12, 2023 https://doi.org/10.3892/ol.2023.13865
Article Number: 279
Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Kansara M, Teng MW, Smyth MJ and Thomas DM: Translational biology of osteosarcoma. Nat Rev Cancer. 14:722–735. 2014. View Article : Google Scholar : PubMed/NCBI
2	Wang T, Wang L, Zhang L, Long Y, Zhang Y and Hou Z: Single-cell RNA sequencing in orthopedic research. Bone Res. 11:102023. View Article : Google Scholar : PubMed/NCBI
3	Wu CC and Livingston JA: Genomics and the immune landscape of osteosarcoma. Adv Exp Med Biol. 1258:21–36. 2020. View Article : Google Scholar : PubMed/NCBI
4	Sun W, Wang B, Qu XL, Zheng BQ, Huang WD, Sun ZW, Wang CM and Chen Y: Metabolism of reactive oxygen species in osteosarcoma and potential treatment applications. Cells. 9:872019. View Article : Google Scholar : PubMed/NCBI
5	Liu W, Zhao Y, Wang G, Feng S, Ge X, Ye W, Wang Z, Zhu Y, Cai W, Bai J and Zhou X: TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling. Redox Biol. 53:1023442022. View Article : Google Scholar : PubMed/NCBI
6	Sarmiento-Salinas FL, Perez-Gonzalez A, Acosta-Casique A, Ix-Ballote A, Diaz A, Treviño S, Rosas-Murrieta NH, Millán-Perez-Peña L and Maycotte P: Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression. Life Sci. 284:1199422021. View Article : Google Scholar : PubMed/NCBI
7	Cheung EC and Vousden KH: The role of ROS in tumour development and progression. Nat Rev Cancer. 22:280–297. 2022. View Article : Google Scholar : PubMed/NCBI
8	Roy K, Wu Y, Meitzler JL, Juhasz A, Liu H, Jiang G, Lu J, Antony S and Doroshow JH: NADPH oxidases and cancer. Clin Sci (Lond). 128:863–875. 2015. View Article : Google Scholar : PubMed/NCBI
9	García JG, Ansorena E, Izal I, Zalba G, de Miguel C and Milagro FI: Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5). J Physiol Biochem. Mar 11–2023.(Epub ahead of print). View Article : Google Scholar
10	Moloney JN, Stanicka J and Cotter TG: Subcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22^phox-derived reactive oxygen species in acute myeloid leukemia. Leuk Res. 52:34–42. 2017. View Article : Google Scholar : PubMed/NCBI
11	Sabharwal SS and Schumacker PT: Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 14:709–721. 2014. View Article : Google Scholar : PubMed/NCBI
12	Marcucci G, Domazetovic V, Nediani C, Ruzzolini J, Favre C and Brandi ML: Oxidative stress and natural antioxidants in osteoporosis: Novel preventive and therapeutic approaches. Antioxidants (Basel). 12:3732023. View Article : Google Scholar : PubMed/NCBI
13	Bai H, Chen G, Fang C, Yang X, Yu S and Hai C: Osteosarcoma cell proliferation and migration are partly regulated by redox-activated NHE-1. J Clin Transl Res. 1:168–179. 2015.PubMed/NCBI
14	Shin SH, Choi YJ, Lee H, Kim HS and Seo SW: Oxidative stress induced by low-dose doxorubicin promotes the invasiveness of osteosarcoma cell line U2OS in vitro. Tumour Biol. 37:1591–1598. 2016. View Article : Google Scholar : PubMed/NCBI
15	Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, et al: The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38:W214–W220. 2010. View Article : Google Scholar : PubMed/NCBI
16	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
17	R-Forge: estimate: Estimate of stromal and immune cells in malignant tumor tissues from expression data. https://R-Forge.R-project.org/projects/estimate/
18	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI
19	Zhang L, Jiao G, Ren S, Zhang X, Li C, Wu W, Wang H, Liu H, Zhou H and Chen Y: Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion. Stem Cell Res Ther. 11:382020. View Article : Google Scholar : PubMed/NCBI
20	Zheng D, Xia K, Yu L, Gong C, Shi Y, Li W, Qiu Y, Yang J and Guo W: A novel six metastasis-related prognostic gene signature for patients with osteosarcoma. Front Cell Dev Biol. 9:6992122021. View Article : Google Scholar : PubMed/NCBI
21	Morgan MJ and Liu ZG: Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 21:103–115. 2011. View Article : Google Scholar : PubMed/NCBI
22	Sun SC: The noncanonical NF-κB pathway. Immunol Rev. 246:125–140. 2012. View Article : Google Scholar : PubMed/NCBI
23	Sahoo BM, Banik BK, Borah P and Jain A: Reactive oxygen species (ROS): Key components in cancer therapies. Anticancer Agents Med Chem. 22:215–222. 2022. View Article : Google Scholar : PubMed/NCBI
24	Parkinson EK, Haferkamp S and Mycielska ME: Cancer cell metabolism. Int J Mol Sci. 23:72102022. View Article : Google Scholar : PubMed/NCBI
25	PavlovaN N, Zhu J and Thompson CB: The hallmarks of cancer metabolism: Still emerging. Cell Metab. 34:355–377. 2022. View Article : Google Scholar : PubMed/NCBI
26	Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI
27	Babior BM, Kipnes RS and Curnutte JT: Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 52:741–744. 1973. View Article : Google Scholar : PubMed/NCBI
28	Yang Y, Bazhin AV, Werner J and Karakhanova S: Reactive oxygen species in the immune system. Int Rev Immunol. 32:249–270. 2013. View Article : Google Scholar : PubMed/NCBI
29	Wu J, Zhang C and Chen L: MiR-511 mimic transfection inhibits the proliferation, invasion of osteosarcoma cells and reduces metastatic osteosarcoma tumor burden in nude mice via targeting MAPK1. Cancer Biomark. 26:343–351. 2019. View Article : Google Scholar : PubMed/NCBI
30	Wang X, Chen K and Zhao Z: LncRNA OR3A4 regulated the growth of osteosarcoma cells by modulating the miR-1207-5p/G6PD signaling. Onco Targets Ther. 13:3117–3128. 2020. View Article : Google Scholar : PubMed/NCBI
31	Chen Q, Sun W, Liao Y, Zeng H, Shan L, Yin F, Wang Z, Zhou Z, Hua Y and Cai Z: Monocyte chemotactic protein-1 promotes the proliferation and invasion of osteosarcoma cells and upregulates the expression of AKT. Mol Med Rep. 12:219–225. 2015. View Article : Google Scholar : PubMed/NCBI
32	Challa TD, Wueest S, Lucchini FC, Dedual M, Modica S, Borsigova M, Wolfrum C, Blüher M and Konrad D: Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO Mol Med. 11:e101242019. View Article : Google Scholar : PubMed/NCBI
33	Zhao H, Chen X, Hu G, Li C, Guo L, Zhang L, Sun F, Xia Y, Yan W, Cui Z, et al: Small extracellular vesicles from brown adipose tissue mediate exercise cardioprotection. Circ Res. 130:1490–1506. 2022. View Article : Google Scholar : PubMed/NCBI
34	Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K and Gotoh Y: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 275:90–94. 1997. View Article : Google Scholar : PubMed/NCBI
35	Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, Koyasu S, Matsumoto K, Takeda K and Ichijo H: ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol. 6:587–592. 2005. View Article : Google Scholar : PubMed/NCBI
36	Gao G and Jian Y: MicroRNA-494 represses osteosarcoma development by modulating ASK-1 related apoptosis complexes. Transl Cancer Res. 9:4121–4130. 2020. View Article : Google Scholar : PubMed/NCBI