CircMAP2K4 Promotes Osteosarcoma Progression through the miR-515-5p/G3BP2 Axis and is Enriched in Tumor-derived Exosomes

Osteosarcoma (OS) is the most common primary malignant bone tumor of adolescents and young adults, and outcomes for patients with metastatic or relapsed disease remain poor. The contribution of exosome-encapsulated circular RNAs (circRNAs) to OS progression remains incompletely defined. We analyzed circMAP2K4 (hsa_circ_0007508) expression in paired OS clinical specimens and cell lines. The biological function of circMAP2K4 was evaluated using Cell Counting Kit-8, EdU incorporation, flow cytometry, Transwell assays, and murine xenograft models. Mechanistic interactions were verified via RNA immunoprecipitation, RNA pull-down, and dual-luciferase reporter assays. Exosomes were isolated from conditioned media to evaluate circMAP2K4 enrichment and the biological effects of exosome preparations from circMAP2K4-overexpressing donor cells. CircMAP2K4 was significantly upregulated in OS tissues and cell lines, displayed a stable, predominantly cytoplasmic, circular topology, and promoted proliferation, migration and invasion while suppressing apoptosis in vitro and in vivo. Mechanistically, circMAP2K4 sponged miR-515-5p and thereby derepressed G3BP2, and re-expression of G3BP2 rescued the phenotypes induced by circMAP2K4 silencing. CircMAP2K4 was enriched in OS-cell exosome preparations, and exosomes isolated from circMAP2K4-overexpressing donor cells enhanced malignant behavior in recipient cells and accelerated xenograft growth. CircMAP2K4 promotes OS progression through the intracellular miR-515-5p/G3BP2 ceRNA axis and is enriched in OS-derived exosomes. Whether the biological effects of exosomes from circMAP2K4-overexpressing donor cells are mediated specifically by transferred circMAP2K4 through the same axis remains to be determined.