https://orcid.org/0000-0002-8475-3696
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Abstract
Background
Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). The mechanism of IDD development and progression is not fully understood. Peripheral biomarkers are increasingly vital non-radioactive methods in early detection and diagnosis for IDD. Nevertheless, less attention has been paid to the role of mitophagy genes in the progress of IDD. This study aimed to identify the mitophagy disease-causing genes in the process of IDD and mitophagy diagnostic biomarkers for IDD.
Methods
Mitophagy-related differentially expressed genes (MRDEGs) related to IDD were investigated by analyzing the microarray datasets of IDD cases from GEO, PathCards and Molecular Signatures Databases. We used R software, WGCNA, PPI, mRNA-miRNA, mRNA-TF, GO, KEGG, GSEA, GSVA and Cytoscape to analyze and visualize the data. We further used ssGSEA for immunoinfiltration analysis to obtain different immune cell infiltration. LASSO model was developed to screen for genes that met the diagnostic gene model requirements. Finally, qRT-PCR, Western blotting and HE were used to verify hub genes and their expression from clinical IDD samples.
Results
We identified 14 MRDEGs and 12 hub genes. GO, KEGG, GSEA and GSVA analyses demonstrated that hub genes were critical for the development of IDD. LASSO diagnostic model consisted of six hub genes, among which SQSTM1, ATG7 and OPTN were significantly different between the two IDD disease subtypes. At the same time, SQSTM1 also had a high correlation with immune characteristic subtypes. The results of qRT-PCR and Western blotting also indicated that these genes were significantly differentially expressed in nucleus pulposus cells (NPCs) of the IDD group.
Conclusion
We explored an association between MRDEGs-associated signature in IDD and validated that hub genes like SQSTM1 might serve as biomarkers for diagnostic and therapeutic targets for IDD. Meanwhile, this study can provide new insights into the functional characteristics and mechanism of mitophagy in the development of IDD.
Graphical Abstract
Abbreviations
IDD, Intervertebral disc degeneration; LBP, Low back pain; DEGs, Differentially expressed genes; MRDEGs, mitophagy-related differentially expressed genes; PPI, Protein-protein interaction; GEO, Gene Expression Omnibus; WGCNA, Weighted gene co-expression network analysis; GSEA, Gene Set Enrichment Analysis; ROC, Receiver operating characteristic curve; ssGSEA, Single sample Gene Set Enrichment Analysis; GSVA, Gene set variation analysis; LASSO, Least absolute shrinkage and selection operator; NPCs, Nucleus pulposus cells; TFs, Transcription factors; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Data Sharing Statement
Any data in this study can be obtained from the corresponding author upon reasonable request. In this study, the datasets analyzed are all publicly available datasets.
Ethics Approval and Consent to Participate
The study was authorized by the Institutional Ethics Committees of The Guangdong Provincial People’s Hospital of Southern Medical University and conformed to the principles of the Declaration of Helsinki (NO. KY-Z-2020-612-03). Written informed consents were obtained from all the patients in this study.
Acknowledgments
We thank all the participants in the Zhujiang Hospital affiliated to Southern Medical University.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.