Wild-type p53-induced phosphatase 1 is a prognostic marker and therapeutic target in bladder transitional cell carcinoma

Abstract

Wild-type p53-induced phosphatase (Wip1) is an established oncogene and is associated with development of multiple forms of human cancer. However, the expression and role of Wip1 in human bladder transitional cell carcinoma (TCC) remains to be elucidated. In the present study, immunohistochemistry demonstrated that Wip1 was overexpressed in bladder TCC tissues compared with corresponding normal bladder tissues in 106 bladder TCC cases (P<0.0001). Furthermore, high expression levels of Wip1 were significantly associated with increasing tumor size (P=0.002), pathological grade (P=0.025), clinical T stage (P=0.001) and lymph nodal metastasis (P=0.003). Kaplan-Meier survival analysis identified that patients with high Wip1 expression levels exhibited a lower overall survival time (P<0.0001), and Cox proportional hazards regression model analysis demonstrated that Wip1 expression was an independent prognostic factor in patients with bladder TCC (P=0.025). In addition, downregulation of Wip1 expression by transfection with small interfering RNA in bladder cancer cells inhibited cell proliferation, invasion and migration (P<0.05), along with the upregulation of p53 protein levels (P<0.05). These findings suggest that Wip1 may function as a potential prognostic marker and therapeutic target in bladder cancer.

Keywords: Wip1; bladder transitional cell carcinoma; invasion; migration; prognosis; proliferation.

Figure 1.

Immunohistochemical analysis of Wip1 expression in the bladder TCC tissues and corresponding normal bladder tissues. (A) High expression of Wip1 in bladder TCC tissue. Low expression of Wip1 in (B) bladder TCC and (C) normal bladder tissues. (D) No expression of Wip1 in normal bladder tissue. Magnification, ×200; scale bar, 50 µm. TCC, transitional cell carcinoma.

Figure 2.

Kaplan-Meier survival analysis of the overall survival time of patients with bladder transitional cell carcinoma. The overall survival time of patients in the high expression group was significantly lower, compared with patients in the low expression group (P<0.0001 vs. low expression group).

Figure 3.

(A) Reverse transcription-quantitative polymerase chain reaction analysis of Wip1 mRNA expression in T24 cells. (B and C) Western blot analysis of Wip1 protein expression levels in T24 cells. (B and D) Western blot analysis of p53 protein expression levels in T24 cells. Wip1 mRNA expression was downregulated in Wip1-siRNA-transfected cells (A, *P<0.05 vs. control). Wip1 protein expression was downregulated in Wip1-siRNA-transfected cells (B and C; *P<0.05 vs. control). P53 protein expression was upregulated in the Wip1-siRNA-transfected cells (B and D; *P<0.05 vs. control). Wip1, wild-type p53-induced phosphatase; siRNA, small interfering RNA.

Figure 4.

MTT assay analysis of cell proliferation. Downregulation of Wip1 inhibited T24 cells proliferation at 24, 48 and 72 h, compared with the control group (*P<0.05 and **P<0.0001 vs. control). Wip1, wild-type p53-induced phosphatase; siRNA, small interfering RNA; OD, optical density.

Figure 5.

Transwell assay analysis of cell invasion and migration. Downregulation of Wip1 inhibited T24 cell invasion and migration, compared with the control group (*P<0.05 vs. control). Magnification, ×200. Wip1, wild-type p53-induced phosphatase; siRNA, small interfering RNA; OD, optical density.