BMSC-derived extracellular vesicles enhance osteosarcoma proliferation and metastasis via the circRNA-0010220/β-catenin pathway

Abstract Osteosarcoma (OS) remains a challenging malignancy with a high propensity for metastasis and poor survival outcomes. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) have emerged as key mediators in the tumor microenvironment, promoting OS progression. This study identifies a novel molecular axis centered on circRNA-0010220 within BMSC-EVs that drives OS aggressiveness. We demonstrate that BMSC-EVs are internalized by OS cells, enhancing their proliferation, migration, and invasion. High-throughput sequencing revealed circRNA-0010220 as the most significantly upregulated circRNA in EV-treated OS cells. Functional studies showed that circRNA-0010220 knockdown in BMSCs attenuated the oncogenic effects of their EVs both in vitro and in vivo. Mechanistically, circRNA-0010220 recruits the histone methyltransferase EZH2 to the CTNNBIP1 promoter, facilitating H3K27me3-mediated epigenetic silencing. The subsequent downregulation of CTNNBIP1 leads to activation of the Wnt/β-catenin signaling pathway. This cascade was consistently observed across gain-of-function and loss-of-function experiments, and pharmacologic inhibition of β-catenin reversed the pro-tumorigenic effects. Our findings elucidate a complete signaling axis from BMSC-EVs to Wnt/β-catenin activation via circRNA-0010220/EZH2/CTNNBIP1, providing new insights into the epigenetic regulation of OS progression and suggesting potential therapeutic targets.