Prognostic roles of the expression of sphingosine-1-phosphate metabolism enzymes in non-small cell lung cancer

Abstract

Background: Sphingosine-1-phosphate (S1P), a bioactive lipid, is generally increased in human nonsmall cell lung cancer (NSCLC). Evidence has shown that the levels of enzymes in S1P metabolism were associated with clinical outcomes in patients with NSCLC. Nevertheless, the roles of mRNA expression of major enzymes (SPHK1, SPHK2 and SGPL1) in S1P metabolism for predicting outcomes in NSCLC patients have not been determined.Methods: "The Kaplan-Meier plotter" (the KM plotter) is an online database which contains gene expression and clinical data of 1,928 NSCLC patients. In this study, we analyzed the relationship between mRNA expression of major enzymes in S1P metabolism and overall survival (OS) in 1,926 NSCLC patients with the KM plotter. Further analyses stratified by smoking history, non-metastasis patents, clinical stages, negative surgical margin, chemotherapy and radiotherapy were also performed.Results: High SPHK1 mRNA expression [hazard ratio (HR) 1.47, 95% confident interval (CI): 1.28-1.68, P=2.6e-08] was significantly correlated to worse OS, but high SPHK2 (0.66, 95% CI: 0.59-0.75, P=1.9e-10) or SGPL1 (HR 0.64, 95% CI: 0.55-0.75, P=8.7e-09) mRNA expression was in favor of better OS in NSCLC patients. Conclusions:The mRNA expression of SPHK1, SPHK2, and SGPL1 is potential predictor of outcomes in NSCLC patients.

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…S1P contributed to the establishment of a pre-metastatic niche, and targeting S1PR1 with fingolimod decreased metastasis to the lungs [ 97 ]. In non-small-cell lung carcinoma (NSCLC), elevated SK1 and SK2 mRNA expression was associated with a worse prognosis in patients, likely due to an increase in S1P produced by the cancer cells [ 98 ]. Zhao et al further considered the role of S1P in NSCLC metastasis through S1PR3.…”

GDC-0349 inhibits non-small cell lung cancer cell growth

“…S1P will promote cell survival and proliferation, while ceramide and sphingosine could induce cell growth arrest and apoptosis. SphK1, which catalyzes ceramide and sphingosine to S1P, is often overexpressed in NSCLC 33 , 57 – 59 and other human cancers 35 , associated with tumorigenesis, cancer progression and resistance to therapies 33 , 35 , 57 – 59 . SphK1 inhibition will lead to ceramide (and sphingosine) accumulation, mediating cancer cell apoptosis 35 .…”

Recent advances in the role of sphingosine 1‐phosphate in cancer

“…Examples of cancers with increased SK2 mRNA or protein in patient tumours include large granular lymphocyte leukaemia [88], papillary thyroid carcinoma [89], cholangiocarcinoma [90], primary glioblastoma [91] and non-small cell lung cancer [92]. In contrast, high SK2 mRNA is associated with increased survival of patients with non-small cell lung carcinoma [93], while SK2 mRNA was reduced in oral cancer [94]. An analysis of available human cancer datasets indicate generally modest upregulation (up to 2.5-fold) of SK2 in many cancers.…”