CXCL14 promotes osteosarcoma cell migration and invasion by inducing epithelial-to-mesenchymal transition.
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Osteosarcoma, an aggressive malignancy of long bones in children and young adults, responds poorly to conventional chemotherapy, and distant metastasis remains the principal cause of death. Here we identify chemokine CXCL14 as a driver of epithelial-to-mesenchymal transition (EMT) and metastatic behavior. CXCL14 expression was markedly higher in osteosarcoma cells than in normal osteoblasts. Knockdown of CXCL14 significantly reduced cell migration and wound closure, accompanied by a shift from spindle-like to cobblestone morphology and restoration of epithelial markers. Recombinant CXCL14 promoted EMT with dose-dependent effects. Western blotting showed CXCL14 suppressed E-cadherin while elevating N-cadherin and vimentin, consistent with EMT induction. Pharmacologic and genetic inhibition revealed that PI3K/AKT, MAPK, and NF-κB signaling cascades mediate CXCL14-driven EMT. In an orthotopic mouse model, silencing CXCL14 retarded tumor growth and reduced mesenchymal marker expression in vivo. Collectively, our results demonstrate that CXCL14 activates PI3K/AKT/MAPK/NF-κB pathways to promote EMT and osteosarcoma progression. Therapeutic targeting of CXCL14 or its downstream signaling may suppress metastasis and improve outcomes for patients with osteosarcoma. These data position CXCL14 as both a biomarker of aggressive phenotypes and an actionable molecular target in pediatric bone cancer patients, warranting preclinical and clinical validation.