CXCL14 drives osteosarcoma cell migration and invasion by inducing epithelial-to-mesenchymal transition

Osteosarcoma (OS) is an aggressive malignancy of long bones primarily affecting children and young adults. Despite standard treatment protocols involving surgery and chemotherapy, patient survival rates remain suboptimal, largely due to the high incidence of distant metastasis. Metastasis is the principal cause of death in OS patients, highlighting a critical need for novel therapeutic strategies that specifically target metastatic progression. Epithelial-to-mesenchymal transition (EMT) is a key cellular process implicated in cancer metastasis, allowing tumor cells to acquire migratory and invasive properties. Understanding the molecular drivers of EMT in osteosarcoma could unlock new therapeutic avenues.

Researchers investigated the role of chemokine CXCL14 in osteosarcoma progression using both in vitro cell models and an orthotopic mouse model. They compared CXCL14 expression in osteosarcoma cells versus normal osteoblasts. In vitro experiments involved knocking down CXCL14 in osteosarcoma cells and assessing changes in cell migration, wound closure, morphology, and epithelial marker expression. Recombinant CXCL14 was applied to cells to observe its dose-dependent effects on EMT. Western blotting was used to analyze key EMT markers like E-cadherin, N-cadherin, and vimentin. Signaling pathway involvement was explored using pharmacologic and genetic inhibition of PI3K/AKT, MAPK, and NF-κB cascades. For in vivo validation, CXCL14 was silenced in an orthotopic mouse model, and effects on tumor growth and mesenchymal marker expression were evaluated.

CXCL14 expression was markedly higher in osteosarcoma cells compared to normal osteoblasts. Knockdown of CXCL14 significantly reduced osteosarcoma cell migration and wound closure, accompanied by a morphological shift from spindle-like to cobblestone and restoration of epithelial markers. Recombinant CXCL14 promoted EMT with dose-dependent effects. Western blotting confirmed that 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. These pathways are crucial for the observed metastatic behaviors. In the orthotopic mouse model, silencing CXCL14 retarded tumor growth and reduced mesenchymal marker expression in vivo. This demonstrates a direct role for CXCL14 in promoting osteosarcoma progression and metastasis.

Collectively, these results demonstrate that CXCL14 activates PI3K/AKT/MAPK/NF-κB pathways to promote EMT and osteosarcoma progression, positioning it as a key driver of aggressive phenotypes.