ANXA3 activates HIF-1α/VEGF Signaling Via the PI3K/AKT/mTOR Pathway to Promote Osteosarcoma Stem Cell-Like Phenotype

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Aberrant Hypoxia-inducible factor 1-alpha (HIF-1α) activation drives cancer stem cell (CSC) phenotypes in malignancies.
• Annexin A3 (ANXA3) is upregulated in osteosarcoma (OS) cells.
• This study investigates ANXA3's role in regulating OS CSC-like properties via the HIF-1α/VEGF signaling pathway.

Purpose of the Study:

• To elucidate the mechanism by which ANXA3 influences CSC-like properties in osteosarcoma.
• To determine the role of the HIF-1α/VEGF signaling pathway in ANXA3-mediated CSC regulation.
• To explore ANXA3 as a potential therapeutic target for osteosarcoma.

Main Methods:

• ANXA3 expression was modulated using lentiviral vectors in osteosarcoma cell lines.
• CSC self-renewal, stemness gene expression, migration, invasion, and chemoresistance were assessed.
• An orthotopic mouse model was used to evaluate ANXA3's in vivo effects on tumor growth and metastasis.
• Signaling pathways, including PI3K/Akt/mTOR-HIF-1α/VEGF, were analyzed using Western blotting, ELISA, and pathway inhibitors.

Main Results:

• ANXA3 overexpression enhanced osteosarcoma sphere formation and stemness, while ANXA3 knockdown reduced these properties and increased cisplatin sensitivity.
• ANXA3 silencing significantly suppressed tumor growth and pulmonary metastasis in vivo.
• Mechanistically, ANXA3 activated the PI3K/Akt/mTOR pathway, leading to increased HIF-1α/VEGF expression.
• Inhibition of PI3K or HIF-1α abrogated ANXA3-induced stemness and chemoresistance.

Conclusions:

• ANXA3 is crucial for maintaining osteosarcoma CSC-like traits through the PI3K/Akt/mTOR-dependent upregulation of the HIF-1α/VEGF pathway.
• Targeting ANXA3 or its downstream effectors offers a potential strategy to reverse CSC phenotypes and overcome chemoresistance in osteosarcoma.