Exploring Mitochondrial Autophagy Dysregulation in Osteosarcoma: Its Implications for Prognosis and Targeted Therapy

Xiangpan Kong; Dawei He; Quan Wang

doi:10.2174/0113862073314265240828170126

Exploring Mitochondrial Autophagy Dysregulation in Osteosarcoma: Its Implications for Prognosis and Targeted Therapy

Comb Chem High Throughput Screen. 2024 Sep 18. doi: 10.2174/0113862073314265240828170126. Online ahead of print.

Authors

Xiangpan Kong^{1

2}, Dawei He^{1

2}, Quan Wang^{3

2}

Affiliations

¹ Department of Urology, Children's Hospital of Chongqing Medical University.
² Chongqing, China, Ministry of Education Key Laboratory of Child Development and Disorders; International Science and Technology Cooperation Base of Child Development and Critical Disorders; National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Higher Institution Engineering Research Center of Children's Medical Big Data Intelligent Application; Chongqing, China.
³ Department of Cardiothoracic Surgery, Children's Hospital of Chongqing Medical University.

PMID: 39297461
DOI: 10.2174/0113862073314265240828170126

Abstract

Objective: This study aimed to investigate the differential expression of mitophagyrelated genes in osteosarcoma patients with distinct prognostic outcomes and explore potential molecular regulatory mechanisms.

Methods: We analyzed microarray data from metastatic and nonmetastatic osteosarcoma patients using the UCSC dataset. Differential gene screening and intersection of mitophagy-related genes were performed using NetworkAnalyst. Random forest and LASSO regression were employed to screen selected genes and establish a risk prediction model. Functional enrichment analysis, protein- protein interaction (PPI) networks, immunoassays, and in vitro experiments were conducted to validate the findings.

Results: Seven differentially expressed genes were identified, and a robust risk prediction model was developed (AUC=0.886). PPI and functional enrichment analyses provided insights into relevant molecules and regulatory pathways. The immunoassay results revealed differences in the immune environment between the metastatic and nonmetastatic groups. Immunohistochemistry demonstrated significant downregulation of EPHA3 expression in the metastatic group, and in vitro experiments indicated that inhibiting EPHA3 increased the proliferative activity and migration ability of osteosarcoma cells.

Conclusion: Our study suggests that the downregulation of EPHA3 may contribute to mitochondrial autophagy dysfunction, thereby increasing the risk of osteosarcoma metastasis.

Keywords: EPHA3.; Osteosarcoma; bioinformatics research; mitophagy.