In this regard, the sphingosine kinase (SPHK)/sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor (S1PR) axis is of interest, since it acts as a master regulator of hypoxia by regulating HIF-1α and HIF-2α protein levels in several human cancer cell lines including VHL-deficient ccRCC [19,20]. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.