Role of Notch signaling pathway in urothelial cancer. Mus musculus

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting, in a context-dependent manner, processes of proliferation, differentiation, and apoptosis1. It has been implicated in human cancer both as an oncogene and a tumor suppressor2. Here we report, for the first time, novel inactivating mutations in the Notch pathway components in over forty percent of the human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the US male population3. Thus far, driver mutations in the FGFR3 and less commonly RAS proteins have been identified4,5. 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 ERK1/2 phosphorylation. In mouse models, genetic inactivation of Notch signaling leads to ERK1/2 phosphorylation resulting in tumorigenesis in the urinary tract. In recent years, the tumor suppressor role of Notch has been recognized by loss-of-function mutations identified in myeloid cancers6 as well as squamous cell carcinomas of the skin, lung7, and the head and neck8,9. Of the 4 Notch receptors (N1-4), only N1 and 2 have been implicated in human cancer. Overall design: two biological replicates from normal and tumor urothelial tissue were hybridized on Affymetrix mm 430 2.0 chips

Notch信号通路（Notch signaling pathway）可通过相邻细胞间的相互作用，以情境依赖的方式正向或负向调控细胞增殖、分化及凋亡过程，进而控制细胞命运¹。该通路在人类癌症中兼具致癌基因与抑癌基因的双重角色²。本研究首次在超40%的受检人类膀胱癌组织中，发现了Notch通路组分的新型失活性突变。膀胱癌是美国男性人群中第四大确诊恶性肿瘤³。迄今为止，学界已在FGFR3蛋白中发现驱动突变，而RAS蛋白的驱动突变则较为少见⁴,⁵。本研究证实，膀胱癌细胞中的Notch激活可通过直接上调双特异性磷酸酶（dual specificity phosphatases, DUSPs）的表达，进而降低ERK1/2的磷酸化水平，最终在体外与体内实验中均抑制细胞增殖。在小鼠模型中，Notch信号通路的遗传失活会导致ERK1/2磷酸化，进而引发尿路肿瘤发生。近年来，研究人员在髓系肿瘤⁶、皮肤、肺⁷及头颈部⁸,⁹的鳞状细胞癌中发现了Notch的功能丧失性突变，从而证实了其抑癌功能。在4种Notch受体（N1-4）中，仅N1与N2与人类癌症相关。实验整体设计：从正常与肿瘤尿路上皮组织中获取两份生物学重复样本，将其在Affymetrix mm 430 2.0芯片上进行杂交。