Role of SphK1 in regulating invasion in HNSCC. (A) SphK1/S1P regulated p-EGFR such that SphK1 overexpression increased p-EGFR and p-ERK and SphK1 knockdown reduced EGFR and ERK phosphorylation. This regulation of p-EGFR putatively affected invasiveness and motility in SCC-25 cells via MMP-2/9 and E-cadherin. (B) SphK1 overexpression increases IL-6 concentration and p-STAT3, while SphK1 knockdown reduces IL-6 and STAT3 activation. (C) S1P1 knockdown reduced invasion in vitro. This may be due to S1P1 regulation of STAT3 as S1P1 knockdown reduced extracellular IL-6 levels and IL-6- and EGF-induced STAT3 activation.