Interestingly, the silencing of Spns2 blocked HIF-2α accumulation in ccRCC cell lines, thus mimicking the effect of the anti-S1P antibody [26] and again highlighting the importance of S1P signaling in the regulation of HIF-2α as a driver of a more aggressive disease in RCC. Here, EPAS1 is linked to nonpapillary renal cell carcinoma.