Abstract
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.
Highlights
Urothelial carcinoma is the most common type of malignancy in both long-term dialysis patients and kidney transplant recipients in Taiwan [1,2,3]
Congenital structural abnormalities of urinary tract, urolithiasis, urothelial carcinoma, and injury to the urinary tract related to infection, surgery, or radiation therapy could lead to hydronephrosis
Urgent relief of chronic hydronephrosis is usually not recommended by urologists because the common complications of hydronephrosis are urinary tract infections and kidney failure, but not the progression of malignancy
Summary
Urothelial carcinoma is the most common type of malignancy in both long-term dialysis patients and kidney transplant recipients in Taiwan [1,2,3]. Hydronephrosis, determined by ultrasonography, is the specific common finding of urothelial carcinoma in these patients [2,3,4]. Congenital structural abnormalities of urinary tract, urolithiasis, urothelial carcinoma, and injury to the urinary tract related to infection, surgery, or radiation therapy could lead to hydronephrosis. All of these factors could lead to the destruction of the delicate tissues that make up the filtration system within the kidneys, which might eventually result in infection, stone formation, tubulointerstitial fibrosis or loss of renal function [5,6,7,8]
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