DUSP3 restrains the progression and stemness property of osteosarcoma through regulating EGFR/STAT3/SOX2 axis

<b>Background:</b> Dual-specificity phosphatase 3 (DUSP3) is a small-molecule dual-specificity phosphatase whose function has not yet been elucidated. This study investigated the effects of DUSP3 on the biological behavior of osteosarcoma and its potential mechanisms. <b>Methods:</b> We performed bioinformatics analysis of DUSP3 using "The Cancer Genome Atlas" and "The Tumor Immune Estimation Resource" databases. The impact of DUSP3 on osteosarcoma biological behavior was evaluated using CCK-8, wound-healing, transwell invasion, and tumor sphere formation assays. Immunoprecipitation assays confirmed the interaction between two proteins. We then established a nude mouse transplantation tumor model to examine the in <i>vivo</i> effects of DUSP3 on osteosarcoma. <b>Results:</b> Overexpression of DUSP3 significantly inhibited osteosarcoma cell proliferation, migration, invasion, and stemness. Conversely, DUSP3 knockdown yielded the opposite results. In an animal model, we administered subcutaneous injections of 143B osteosarcoma cells overexpressing DUSP3, and the results indicated that the overexpression of DUSP3 impaired osteosarcoma growth. <b>Conclusion:</b> Our findings indicate that DUSP3 could be an independent prognostic determinant in individuals diagnosed with osteosarcoma. Through modulating the EGFR/STAT3/SOX2 axis, DUSP3 restrains osteosarcoma cell growth, migration, invasion, and stemness. Therefore, targeting DUSP3 may serve as an effective therapeutic target in osteosarcoma treatment.