Considering the critical role of HIF-2α in ccRCC,29, 31 the molecular mechanisms of HIF-2α regulation by SphK1 were further investigated in three ccRCC cell lines, representing the sub-groups found in human clinic (expressing either HIF-1α and HIF-2α or HIF-2α alone). The gene discussed is EPAS1; the disease is nonpapillary renal cell carcinoma.