Therefore, the aim of this work was to investigate the antineoplastic effect of metformin against ccRCC cell lines, namely Caki-1 and Caki-2, and to explore if there is a differential selectivity in the VHL status of these two cell lines by evaluating HIF-1α and HIF-2α expression. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.