Semaphorin 3F Serves as a Tumor Suppressor in Esophageal Squamous Cell Carcinoma and is Associated With Lymph Node Metastasis in Disease Progression

Background: Esophageal squamous cell carcinoma is one of the leading aggressive malignancies with high mortality. Semaphorin 3F has been reported to be involved in lymphangiogenesis by interacting the vascular endothelial growth factor C/neuropilin 2 axis. This study aimed to assess the clinical and functional role of semaphorin 3F and preliminarily evaluate the relationship between semaphorin 3F and lymph node metastasis in esophageal squamous cell carcinoma. Methods: The messenger RNA expression of semaphorin 3F was analyzed using quantitative real-time polymerase chain reaction. The expression differences of semaphorin 3F between patients having esophageal squamous cell carcinoma with and without lymph node metastasis were assessed, and the correlation of semaphorin 3F with vascular endothelial growth factor C and neuropilin 2 was estimated. The prognostic value of semaphorin 3F was evaluated using Kaplan-Meier survival curves and Cox regression analysis. Gain- and loss-functional cell experiments were performed to explore the biological function of semaphorin 3F, vascular endothelial growth factor C, and neuropilin 2. Results: The messenger RNA expression of semaphorin 3F was reduced in esophageal squamous cell carcinoma tissues compared with normal tissues, and lower semaphorin 3F expression was observed in patients having esophageal squamous cell carcinoma with positive lymph node metastasis. Semaphorin 3F expression was associated with lymph node metastasis and negatively correlated with vascular endothelial growth factor C and neuropilin 2. Lower semaphorin 3F expression was related to a poor overall survival of esophageal squamous cell carcinoma and served as an independent prognostic indicator. In esophageal squamous cell carcinoma cells, semaphorin 3F messenger RNA expression was also decreased compared with normal cells, and the overexpression of semaphorin 3F could significantly inhibit cell proliferation, migration, and invasion. The downregulation of vascular endothelial growth factor C and neuropilin 2 could inhibit cell proliferation, migration, and invasion of esophageal squamous cell carcinoma cells. Conclusion: All data indicate that semaphorin 3F serves as a potential prognostic biomarker and tumor suppressor of esophageal squamous cell carcinoma and may be involved in the lymph node metastasis development through regulating neuropilin 2.