A new tumor suppressor role for the Notch pathway in bladder cancer

作者：Rampias Theodoros; Vgenopoulou Paraskevi; Avgeris Margaritis; Polyzos Alexander; Stravodimos Konstantinos; Valavanis Christos; Scorilas Andreas; Klinakis Apostolos^*

来源：Nature Medicine, 2014, 20(10): 1199-1205.

DOI：10.1038/nm.3678

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner(1). This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor(2). Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States(3). Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified(4,5). We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

• 出版日期2014-10