Considering the critical role of HIF-2α in ccRCC pathogenesis, we further detailed the molecular mechanisms of HIF-2α regulation by the SphK1/S1P signaling in various ccRCC models representing the sub-groups found in human clinic,29 and by taking advantage of the features of A498 and 786-O VHL-defective cells that only express HIF-2α,38, 39 and not HIF-1α we previously reported to be regulated by SphK1 signaling.32 The gene discussed is VHL; the disease is nonpapillary renal cell carcinoma.