Upregulated ATG4B Predicts Poor Prognosis and Correlates with Angiogenesis in Osteosarcoma

Background: Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Patients with metastatic OS experience significantly poorer outcomes, largely due to resistance to chemotherapy. Between 35-45% of these patients do not respond to standard chemotherapeutic treatments, resulting in a very low 5-year survival rate of only 5-20%. This resistance often leads to treatment failures and unfavorable prognoses, highlighting the critical need for new therapeutic targets to improve treatment strategies. Autophagy-related gene 4 B (ATG4B) is a crucial cysteine protease for autophagosome formation. It is overexpressed and correlates with poor prognosis in various cancers. However, the relationship between ATG4B expression and angiogenesis in osteosarcoma remains unexplored. This study investigates the expression levels of ATG4B and VEGF in osteosarcoma and their correlation with clinicopathological data. Materials and Methods: The study included 67 paraffin-embedded osteosarcoma tissue samples. ATG4B and VEGF expression levels were assessed via immunohistochemistry, and their associations with clinicopathological variables were statistically analyzed. Additionally, ATG4B gene expression in osteosarcoma was examined using GEO data sets from https://www.ncbi.nlm.nih.gov. Results: The analysis showed that ATG4B and VEGF were expressed in 79.1% and 74.6% of the osteosarcoma samples, respectively. There was a significant positive correlation between ATG4B expression and tumor size, tumor stage, and histological response to neoadjuvant chemotherapy, with p-values of 0.013, 0.008, and 0.022, respectively. VEGF expression also significantly correlated with tumor size, tumor stage, and the presence of distant metastasis at diagnosis, with p-values of 0.022, 0.044, and 0.013, respectively. A notable positive correlation between ATG4B and VEGF expression levels was observed (p=0.002), supported by the GEO dataset analysis. Conclusions: The results suggest that ATG4B acts as a tumor promoter in osteosarcoma, indicating its potential as a therapeutic target to inhibit tumor growth. Elevated ATG4B levels may also serve as a marker for poor prognosis. Additionally, VEGF overexpression is linked to a higher likelihood of pulmonary metastasis and worse overall prognosis. The positive correlation between ATG4B and VEGF suggests that the absence of both markers could be indicative of a better chemotherapy response, offering insights into potential new treatment approaches.