Downregulation of Semaphorin-3F is associated with poor prognostic significance in osteosarcoma patients

The secreted axonal guidance molecular, Semaphorin-3F (SEMA3F), is widely expressed outside the central nervous system and inhibits tumor growth and metastasis. However, the role of SEMA3F expression in the osteosarcoma prognosis has not been elaborated. This study aimed to evaluate SEMA3F expression level in osteosarcoma and assess its prognostic value for patients. SEMA3F protein expression was detected by immunohistochemistry (IHC) in 112 cases of osteosarcoma. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of SEMA3F. The results showed that the overall survival and metastasis-free survival of patients with negative SEMA3F expression were significantly shorter than patients with positive expression (both P<0.01). Multivariate Cox analysis identified SEMA3F expression as an independent prognostic factor to predict favorable overall survival and metastasis-free survival (both P<0.01). When endogenous SEMA3F expression was knocked down by siRNAs, cell proliferation, colony formation, migration and invasion in osteosarcoma cell lines were obviously promoted. Meanwhile, SEMA3F knockdown decreased E-cadherin expression but increased the expression of N-cadherin and β-Catenin, which indicated that SEMA3F could inhibit epithelial-mesenchymal transition (EMT). Mechanically, knockdown of SEMA3F inhibited GSK-3β protein expression and promoted the expression of β-Catenin and c-myc proteins. GSK-3β is a key upstream suppressor of β-Catenin and c-myc expression is an indicator of Wnt/β-Catenin activity. Therefore, these results suggest that down-regulated SEMA3F may promote EMT, migration, invasion and metastasis of osteosarcoma via activating Wnt/β-Catenin signaling. In conclusion, SEMA3F is downregulated and associated with prognosis of patients, indicating that SEMA3F may be a potential prognostic biomarker and therapeutic target for osteosarcoma.