Hydronephrotic Urine in the Obstructed Kidney Promotes Urothelial Carcinoma Cell Proliferation, Migration, Invasion through the Activation of mTORC2-AKT and ERK Signaling Pathways

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.

Nucleosome Assembly Protein 1-Like 1 (Nap1l1) Regulates the Proliferation of Murine Induced Pluripotent Stem Cells

“…Su CC reported that Tanshinone IIA inhibits the proliferation of human gastric cancer cells by G2/M phase arrest which results from inhibition of ERK [26]. Chang CH reported that hydronephrotic urine promotes urothelial carcinoma cell proliferation or migration through the activation of AKT and ERK signaling pathway to decrease the expression of p21 and p27 [40]. These results are similar to our study.…”

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Down-regulation of tumor endothelial marker 8 suppresses cell proliferation mediated by ERK1/2 activity

“…The progression of osteosarcoma is linked to the activation of many signaling pathways, one of which is MAPK, MEK and ERK1/2 signaling 21 . ERK1/2 activity plays an important role in tumorigenesis via the regulation of a variety of biologic processes, such as apoptosis, proliferation and migration through induction of the cyclin dependent kinase (CDK) inhibitors, including p21 and p27 22 23 24 . As our previous study 12 demonstrated, ERK1/2 played an important role in the development of osteosarcoma.…”