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PEA15 promotes osteosarcoma progression and cisplatin resistance by modulating autophagy through the FABP3-TNF
Yuanxiang Peng1,2,3, Feng Cai2,3, Lang Liu2,3
1The First Affiliated Hospita1, Jiangxi Medica1 College, Nanchang University, Nanchang 330008, China.
Abstract:
Osteosarcoma (OS), a primary malignant bone tumor, is characterized by resistance to chemotherapeutic agents such as cisplatin (DDP), posing a major obstacle to effective treatment. Tumor cells often exploit autophagy to survive chemotherapeutic stress, which contributes to this resistance. Using weighted gene co-expression network analysis (WGCNA), this study screened for autophagy-related genes associated with OS prognosis and identified PEA15 as a key indicator of poor outcomes. Through gene knockdown and overexpression experiments in OS cell lines and xenograft models, we found that PEA15 promotes tumor progression. Mechanistically, RNA sequencing revealed that PEA15 inhibits autophagy and apoptosis by modulating the downstream target FABP3 and the associated TNF signaling pathway. Notably, silencing PEA15 in resistant OS cells enhanced their sensitivity to cisplatin by activating autophagy. These findings identify the PEA15-FABP3-TNF signaling axis as a key pathway regulating chemoresistance in OS, suggesting that targeting PEA15 could be a promising therapeutic strategy to improve patient outcomes.
Insights
PEA15 promotes osteosarcoma progression and cisplatin resistance by inhibiting autophagy. Silencing PEA15 restores sensitivity to chemotherapy, offering a potential therapeutic target for bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Osteosarcoma (OS) exhibits resistance to chemotherapy, particularly cisplatin (DDP).
- Tumor cells utilize autophagy to survive chemotherapy, contributing to treatment failure.
- Identifying novel therapeutic targets is crucial for improving OS patient outcomes.
Purpose of the Study:
- To identify autophagy-related genes impacting OS prognosis.
- To investigate the role of PEA15 in osteosarcoma progression and chemoresistance.
- To elucidate the molecular mechanisms underlying PEA15-mediated chemoresistance.
Main Methods:
- Weighted gene co-expression network analysis (WGCNA) for gene screening.
- Gene knockdown and overexpression in OS cell lines and xenograft models.
- RNA sequencing to identify downstream targets and signaling pathways.
Main Results:
- PEA15 was identified as a key gene associated with poor prognosis in OS.
- PEA15 promotes OS tumor progression by inhibiting autophagy and apoptosis.
- PEA15 exerts its function by modulating the FABP3 and TNF signaling pathway.
- Silencing PEA15 in cisplatin-resistant OS cells re-sensitizes them to DDP via autophagy activation.
Conclusions:
- The PEA15-FABP3-TNF signaling axis is critical for regulating chemoresistance in osteosarcoma.
- Targeting PEA15 presents a promising therapeutic strategy to overcome cisplatin resistance in OS.
- Modulating autophagy through PEA15 inhibition could enhance the efficacy of chemotherapy for bone cancer patients.
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