Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules

Abstract

Studies suggest a tumor-promoting function of sphingosine kinase 1 (SphK1) in some types of human tumors, however, its effect on colon cancer is still unclear. The aims of this study were to investigate the roles of SphK1 in the progression and tumor cell phenotypic changes in colon cancer. Moreover, the focal adhesion kinase (FAK) pathway and the expression of intercellular adhesion molecule‑1 (ICAM‑1) and vascular cell adhesion molecule‑1 (VCAM‑1) were detected to explore the mechanisms of SphK1 action. In this study, the expression of SphK1, FAK and phospho-FAK (p-FAK) was analyzed in 66 surgical specimens of primary colon cancer and matched adjacent normal tissues by immunohistochemistry and western blotting. In addition, N,N-dimethylsphingosine (DMS), SphK1 DNA and shRNA transfection were used to regulate the expression and activity of SphK1 in the LOVO colon cancer cell line. Tumor cell phenotypic changes were analyzed by cell viability, invasion and apoptosis assays. Results showed that the expression of SphK1, FAK and p-FAK in colon cancer tissues were significantly stronger compared to those in matched normal tissues. There was a close correlation between the expression of SphK1 and FAK or p-FAK and the co-expression of SphK1, FAK and p-FAK significantly associated with histological grade, Dukes' stage, lymph node metastasis and distant metastasis. Overexpression of SphK1 after DNA transfection enhanced tumor cell viability and invasiveness, but suppressed cell apoptosis. In contrast, suppression of SphK1 by DMS and shRNA reduced tumor cell viability and invasiveness, but promoted cell apoptosis. The expression of FAK, p-FAK, ICAM-1 and VCAM-1 in LOVO cells were increased with the overexpression of SphK1 but decreased with the suppression of SphK1. These findings indicate that SphK1 regulates tumor cell proliferation, apoptosis and invasion, which ultimately contributes to tumor progression and malignancy phenotype in colon cancer. FAK pathway, ICAM-1 and VCAM-1 may play critical roles in this SphK1‑mediated effect.