[Sphingosine kinase-1 regulates migration and invasion of gastric cancer cells via targeting the nuclear factor-κB signaling pathway].

Objective: To investigate the role of sphingosine kinase-1 (SPHK1) in regulating migration and invasion of gastric cancer (GC) cells.

Methods: TIMER2.0, GEPIA and HPA databases were used to investigate SPHK1 expression in GC, and its association with prognosis of the patients was analyzed using Kaplan-Meier Plotter database. In 40 clinical GC and adjacent tissue samples, SPHK1 and MKI67 expressions were detected with immunohistochemistry, Western blotting, and RT-qPCR. Gene enrichment pathway analysis was conducted to explore the biological functions of SPHK1. In HGC-27 and MGC-803 cells, the effects of lentivirus-mediated SPHK1 knockdown or overexpression on cell migration and invasion and expressions of key proteins in the nuclear factor-κB (NF-κB) signaling were evaluated using cell scratch test, Transwell assays and Western blotting. The changes in tumorigenic capacity of the transfected GC cells were evaluated in nude mice.

Results: SPHK1 was highly expressed in GC tissues in negative correlation with overall survival, overall survival after progression, and relapse-free survival of the patients (all P<0.001). In clinical GC samples, SPHK1 and MKI67 expressions showed a positive correlation (P= 0.00049) and were both significantly up-regulated (P<0.001). Gene enrichment pathway analysis suggested the involvement of SPHK1 in cell adhesion, migration, angiogenesis and the NF-κB pathway (P<0.05). In the cell experiment, SPHK1 knockdown significantly decreased while SPHK1 overexpression enhanced migration and invasion abilities of the GC cells. SPHK1 positively regulated the expressions of phosphorylated P65 (P-P65), VEGFA and IL-17, and blocking the NF-κB pathway by PDTC significantly lowered migration and invasion ability of the cells. In nude mice, the GC cells with SPHK1 knockdown resulted in significantly reduced tumor size and mass, while the SPHK1-overexpressing cells showed enhanced tumorigenicity.

Conclusion: SPHK1 regulates migration and invasion of GC cells via the NF-κB signaling pathway and may serve as a potential diagnostic marker for GC progression.