Abstract
Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo. In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin. Furthermore, suberoylanilide hydroxamic acid (SAHA, a histone deacetylase [HDAC] inhibitor) induced acetylation of NOTCH3, downregulated Notch 3, prevented urothelial cancer cell proliferation, and induced cell cycle arrest. Taken together, these data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer.
Highlights
Bladder cancer is the ninth most common malignancy worldwide, with estimated 386,300 new cases and 150,200 deaths from bladder cancer in 2008 [1]
The results showed that Notch3 was expressed in adjacent non-tumor tissue but that its expression was much higher in tumor tissues (Figure 1A–1B)
Notch3 protein levels were significantly higher in urothelial cancer tissues compared to non-tumor tissues (P < 0.05). These results demonstrated that Notch3 expression was increased in human urothelial cancer
Summary
Bladder cancer is the ninth most common malignancy worldwide, with estimated 386,300 new cases and 150,200 deaths from bladder cancer in 2008 [1]. In the United States, medical expenses for bladder cancer ranks first among all malignancies, with a mean of $202,000 per patient, i.e. 2 folds compared with lung cancer costs [3]. This imposes a heavy economic burden on the society. The biological processes of bladder cancer are very complex, with several features such as heterochrony and heterotopy, high recurrence, multiple tumors, progression to invasive bladder cancer, and metastasis. Targeting agents that promote bladder cancer development and progression could constitute a promising option
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