Obstructive nephropathy is the most common presentation of urothelial
carcinoma. The role of the urine in the obstructed kidney namely "hydronephrotic urine" in urothelial
carcinoma has not been extensively explored. This study aims to evaluate whether hydronephrotic urine in the obstructed kidney could promote urothelial
carcinoma. The hydronephrotic urine was collected from the obstructed kidneys of Sprague-Dawley rats induced by different periods of unilateral
ureteral obstruction (UUO). By the inhibition of
LY294002 and
PD184352, we confirm that hydronephrotic urine promotes urothelial
carcinoma cell (T24) and immortalized normal urothelial cells (E6) proliferation, migration and invasion in a dose-dependent manner through the activation of the mTORC2-AKT and ERK signaling pathways. Hydronephrotic urine also increases the expression of cyclin-D2,
cyclin-B and CDK2. It also decreases the expression of p27 and p21 in both urothelial
carcinoma cells and normal urothelial cells. By the
protein array study, we demonstrate that many
growth factors which promote
tumor cell survival and
metastasis are over-expressed in a time-dependent manner in the hydronephrotic urine, including beta-FGF, IFN-γ,
PDGF-BB, PIGF, TGF-β,
VEGF-A,
VEGF-D and
EGF. These results suggest that hydronephrotic urine promotes normal and malignant urothelial cells proliferation, migration and invasion, through the activation of the mTORC2-AKT and ERK signaling pathways. Further investigation using live animal models of
tumor growth may be needed to clarify aspects of these statements.