Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, plays a crucial role in tumorigenesis. It mediates its function through S1P receptors. A few components of the S1P signaling pathway, such as sphingosine kinase 1 (SphK1) and S1P receptor 1 (S1PR1), have been shown to contribute to lung carcinogenesis. In the present study, using web-based computational tools, we assessed the prognostic roles of eight S1P metabolizing enzymes and five S1P receptors in non-small-cell lung cancer (NSCLC) patients. Except for SPHK1, low expression of S1P metabolizing enzymes was correlated with worse overall survival (OS) in NSCLC patients. Moreover, lower expression of lipid phosphate phosphatase-1 and – 3 (PLPP1 and PLPP3) was significantly associated with worse OS in lung adenocarcinoma (LUAD) and non-smoker NSCLC patients. Furthermore, the UALCAN database analysis showed that mRNA and protein expression of PLPP3 and S1PR1 are significantly down regulated in primary tumors due to hypermethylation of their respective promoters. Expression of PLPP3, S1PR1, and S1PR4 was positively correlated with tumor-infiltrating immune cells in NSCLC patients. These results indicate that S1P signaling genes play a critical prognostic role in LUAD patients. Therefore, this gene signature could be used to predict their prognosis more accurately.
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