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.

骨肉瘤（OS）是骨的主要恶性肿瘤，具有早期转移的趋势。设计新的治疗方法需要了解调节OS转移的途径。精子相关抗原5（SPAG5）被上调，并在多种人类癌症中起潜在的肿瘤启动子的作用，但尚未在OS中进行研究。在本研究中，结果显示SPAG5在OS组织中的表达上调，而SPAG5的过度表达显然与OS患者的恶性表型和不良的生存率有关。多变量分析还显示，SPAG5过表达是OS患者预后不良的独立预后因素。功能分析表明SPAG5沉默在体外显着抑制OS细胞的侵袭和迁移。此外，敲低OS细胞中SPAG5的表达可在体内抑制肺转移。此外，我们还发现SPAG5沉默抑制OS细胞的上皮-间质转化（EMT）过程。此外，我们的结果表明SPAG5通过增加基质金属蛋白酶2（MMP2）表达来促进OS转移，并证明MMP2对于SPAG5在OS细胞中的促转移作用至关重要。从机制上讲，我们发现SPAG5通过调节FOXM1（叉头盒M1）降解来增强FOXM1的蛋白质稳定性，从而调节MMP2的表达。这些发现共同描述了SPAG5-FOXM1-MMP2轴在OS细胞迁移和转移形成调控中的作用。我们提供了一个新的证据，SPAG5可以作为骨肉瘤患者的预后指标和潜在的治疗靶标。