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. 2025 Apr 25;37(1):24.
doi: 10.1186/s43046-025-00269-z.

Upregulated ATG4B predicts poor prognosis and correlates with angiogenesis in osteosarcoma

Elzahraa Ibrahim Mohamed Khalil  1 , Fatma El Zahraa Ammar Mohamed  2   3 , Rehab Kamal Mohamed  3
Affiliations

Upregulated ATG4B predicts poor prognosis and correlates with angiogenesis in osteosarcoma

Elzahraa Ibrahim Mohamed Khalil et al. J Egypt Natl Canc Inst. .

Abstract

Background: Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. Between 35 and 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 failure 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 OS remains unexplored. This study investigated the expression levels of ATG4B and VEGF in OS and their correlation with clinicopathological data.

Materials and methods: This study included 67 paraffin-embedded OS 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 OS was examined via GEO datasets from https://www.ncbi.nlm.nih.gov .

Results: 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 was 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), which was supported by the GEO dataset analysis. High ATG4B and VEGF overexpression were significantly associated with worse overall survival by univariate analysis.

Conclusions: The results suggest that ATG4B acts as a tumor promoter in OS, 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 greater likelihood of pulmonary metastasis and a 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.

Keywords: ATG4B; Angiogenesis; Autophagy; Osteosarcoma; VEGF.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki. This project was approved by the Ethics Committee of Minia University, Faculty of Medicine, Institutional Review Board (MUFMIRB 1204/07/2024). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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