SPAG5 promotes osteosarcoma metastasis via activation of FOXM1/MMP2 axis.

Osteosarcoma (OS) is a primary malignancy of bone with a tendency to metastasize early. An understanding of the pathways that regulate OS metastasis is required for the design of novel treatment approaches. Sperm-associated antigen 5 (SPAG5) is upregulated and functions as a potential tumor promoter in diverse human cancers, but has yet to be investigated in the OS. In the present study, results showed that SPAG5 expression is upregulated in OS tissues, and SPAG5 overexpression is obviously associated with the malignant phenotype and poor survival in patients with OS. Multivariate analyses also revealed that SPAG5 overexpression is an independent prognostic factor for poor outcome of patients with OS. The functional assay indicated that SPAG5 silencing significantly inhibits the invasion and migration of OS cells in vitro. Additionally, knockdown of SPAG5 in OS cells suppresses lung metastasis in vivo. Further, we also found that SPAG5 silencing inhibits the epithelial-mesenchymal transition (EMT) process of OS cells. Moreover, our results indicated that SPAG5 promotes OS metastasis by increasing matrix metalloproteinase-2 (MMP2) expression, and demonstrated that MMP2 is crucial for the pro-metastasis role of SPAG5 in OS cells. Mechanistically, we identified that SPAG5 regulates MMP2 expression by modulating FOXM1 (Forkhead box M1) degradation to enhance the protein stability of FOXM1. Collectively, these findings describe the effects of SPAG5-FOXM1-MMP2 axis in the regulation of OS cell migration and metastasis formation. We provide a novel evidence that SPAG5 may serve as a prognostic indicator and potential therapeutic target for patients with osteosarcoma.