Moreover, our study first demonstrated in ccRCC that (1) ERK5 is regulated not only by pVHL but also by miR-143; (2) ERK5 inhibition suppresses cell viability in highly ERK5-expressed ccRCC cell and endothelial cells; (3) ERK5 inhibition suppressed the expression of anti-apoptotic protein BCL2 and induced apoptosis; (4) ERK5 inhibitor XMD8-92 suppressed tumor growth in xenograft model. This evidence concerns the gene VHL and nonpapillary renal cell carcinoma.