Decrease in stathmin expression by arsenic trioxide inhibits the proliferation and invasion of osteosarcoma cells via the MAPK signal pathway

Osteosarcoma (OS) is the most common type of malignant bone tumor in children and adolescents. In total, 40-50% of patients with OS experience metastasis, and thus have a poor prognosis. Our previous study demonstrated that arsenic trioxide (As₂O₃) combined with doxorubicin [also known as Adriamycin (ADM)] significantly inhibited OS cell proliferation by downregulating stathmin expression. The present study investigated the effect and mechanism of stathmin expression on OS cell invasion. It was identified that the expression of stathmin was increased in human ADM-resistant OS MG63 (MG63/dox) cells compared with the level in the normal osteoblast hFoB1.19cell line using western blot analysis. Lentiviral-mediated small hairpin RNA (shRNA) was constructed to silence stathmin expression of MG63/dox cells. In transwell assay, stathmin-knockdown significantly suppressed migration and invasion in MG63/dox cells. As₂O₃ combined with ADM inhibited the migration and invasion of MG63/dox cells, and was associated with the downregulation of phosphorylated-mitogen-activated protein kinase (MAPK) 1 and β-catenin, and upregulation of phosphorylated-MAPK8 and E-cadherin. In addition, stathmin-knockdown significantly suppressed tumor growth and increased E-cadherin expression in a xenograft nude mouse model. Taken together, these data suggested that As₂O₃ combined with ADM inhibited stathmin-mediated invasion via the MAPK pathway. Elucidation of the mechanism for stathmin downregulation by As₂O₃ may provide novel insights into the mechanism of OS metastasis.