High expression of spindle assembly checkpoint proteins CDC20 and MAD2 is associated with poor prognosis in urothelial bladder cancer

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Abstract
Aneuploidy is a result of the abnormal expression of spindle assembly checkpoint (SAC) proteins and resulting abnormal spindle function during mitosis. High expression of cell division cycle 20 homolog (CDC20) and mitotic arrest defective protein 2 (MAD2), key components of the SAC, has been reported in various carcinomas. However, the clinicopathological significance of CDC20 and MAD2 expressions in urothelial carcinoma of the human bladder (UCB) is unknown. We therefore studied the expression of CDC20 and MAD2 in UCB specimens by immunohistochemistry. High expression of CDC20 and MAD2 was observed in 59.0 % (200/339) and 51.0 % (173/339) of UCB cases, respectively. Most high-grade tumor cells exhibited diffuse nuclear and/or cytoplasmic staining for CDC20 and MAD2, whereas most low-grade tumor cells and normal urothelial cells were not stained. CDC20 overexpression was associated with advanced age (p = 0.010), high grade (p < 0.001), advanced stage (p < 0.001), non-papillary growth pattern (p < 0.001), and distant metastasis (p = 0.042). Similarly, high MAD2 expression correlated with high grade (p < 0.001), advanced stage (p < 0.001), and non-papillary growth pattern (p < 0.001). In univariate survival analyses, high CDC20 expression correlated with shorter recurrence-free survival (RFS) (p = 0.032) and poorer overall survival (OS) (p = 0.007) in patients with UCB, whereas high MAD2 expression was associated with poorer OS (p = 0.008). In multivariate analyses, high CDC20 expression correlated with shorter RFS of patients with Ta stage UCB (hazard ratio, 1.91; p = 0.01). In conclusion, increased expression of CDC20 and MAD2 is related to poor prognosis of UCB.

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