Construction and validation of a prognostic model for osteosarcoma patients based on autophagy-related genes

Abstract

Background Osteosarcoma is the most frequent primary bone malignancy with a poor prognosis because of pulmonary metastasis. Autophagy is strongly associated with tumor metastasis, and it is valuable to construct an autophagy-related gene risk model for predicting the prognosis of osteosarcoma. Methods We obtained ARGs from the Human Autophagy Database and RNA-sequencing data of osteosarcoma patients from the Gene Expression Omnibus (GEO) database. Subsequently, univariate and multivariate cox regression analyses were performed to construct a three-gene prognostic model and its accuracy was further confirmed in the Therapeutic Applications Research to Generate Effective Treatments (TARGET) database. Afterward, we detected the expression levels and effects on osteosarcoma cells metastasis of MYC and MBTPS2, which were involved in the model. Results In both training and verification cohorts, patients with lower risk scores had longer OS, and the model was identified as an independent prognostic factor in osteosarcoma. Besides, the ROC curve demonstrated the reliability of the model. Furthermore, RT-qPCR, Western Blotting and IHC results indicated that MYC and MBTPS2 were differently expressed in osteosarcoma tissues and cell lines. MYC knockdown or MBTPS2 overexpression prevented the capacity of migration and invasion in osteosarcoma cell lines through inhibiting cellular autophagy. Conclusion The risk model based on three ARGs had a strong ability to predict the prognosis of osteosarcoma patients. Our findings also suggested that MYC and MBTPS2 were two major factors regulating autophagy in osteosarcoma, and could serve as potential therapeutic targets for osteosarcoma.

Autophagy Modulation as a Potential Therapeutic Strategy in Osteosarcoma: Current Insights and Future Perspectives

“…In addition, AKT cooperates with EGFR in the inhibition of autophagy through the phosphorylation of Beclin1 in a manner independent of the mTORC1 pathway [ 28 ]. Under unperturbed conditions, Beclin1 binds to Bcl2 (B-cell lymphoma 2), modulates the PI3K Complex, and inhibits autophagy, whereas, under stress conditions, the interaction between Beclin1 and Bcl2 is disrupted by Beclin1 phosphorylation [ 5 ].…”

“…In addition, the activation of N-terminal c-Jun kinase (JNK) due to ROS leads to phosphorylation and the inactivation of Bcl2, thereby promoting autophagy [ 5 ]. HMGB1 (High Mobility Group Box 1) plays a positive role in autophagy induction during oxidate stress via its translocation from the nucleus to the cytosol and its interaction with the autophagy protein Beclin1, displacing Bcl2 [ 29 ].…”

“…However, it is important to note that autophagy has a dual role in radioresistance, as it can both prevent and induce cell death. As a result, researchers have increasingly focused on searching for clinically effective radiosensitizers [ 5 ].…”

“…modulates the PI3K Complex, and inhibits autophagy, whereas, under stress conditions, the interaction between Beclin1 and Bcl2 is disrupted by Beclin1 phosphorylation [5].…”

“…Due to tumor radioresistance, radiotherapy is rarely used to treat OS [ 3 ]. Despite these advances, overall survival has reached a bottleneck [ 5 ]. Since no significant advances in treating the disease have been made during recent years, the search for new therapeutic strategies is justified, where autophagy has become an exciting option due to its relationship with multiple biological processes in OS.…”