Our results provide the first evidence for the overexpression of PIK3R2 in aggressive Xp11.2 tRCC and show that suppressing PIK3R2 by LY294002 in Xp11.2 tRCC cell lines eventually leads to a decrease in proliferation, migration, and invasion abilities, similar to observations in lung cancer cell lines. Here, PIK3R2 is linked to renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.