SPHK1 promoted metastasis via activation of the EGFR pathway. To glean mechanistic insight into the role of SPHK1 in invasion and metastasis, we surveyed potential links between SPHK1 and key molecules of known relevance to invasion. (A) Western blotting indicated that the expression of SPHK1 was significantly correlated with the phosphorylation of EGFR. (B) Correspondingly, SPHK1 RNAi decreased the phosphorylation of EGFR in EC9706-P4 and KYSE2 cells. (C) We clustered the upregulated genes in the SPHK1 overexpression clones compared with control cells. Expression of SPHK1 was significantly correlated with the expressions of IL6, ITGA2, IL8, EREG, MMP1, ITGA5, MMP3 and AREG. Most of the genes are the downstream genes of EGFR pathway, and most of them have been associated with the invasion of cancer cells. (D) Western blotting indicated that the ligands of EGFR (EGF, EREG, and AREG) induced the expression of SPHK1 protein.