膀胱癌在泌尿系肿瘤的发病率和死亡率均为全球第二位，其中非肌层浸润性膀胱癌（NMIBC）向肌层浸润性膀胱癌（MIBC）恶性进展的预测，以及对晚期膀胱癌的分子生物治疗是目前泌尿外科研究的热点。本课题组的前期研究发现Notch通路在膀胱癌中的表达随恶性程度的上升而下调。γ-分泌酶复合体为多个信号通路上的关键切割酶，其酶活性催化亚单位Presenilin（PS1和PS2）已被证明可独立参与多个病生理过程，然而PS在膀胱癌中的研究尚处于空白。我们的初步研究显示PS1在膀胱癌中的表达不仅与恶性程度呈正相关，并且其在不同恶性转归膀胱癌组织中的表达可能具有预测价值；同时体外实验证实了抑制PS导致高恶度膀胱癌细胞周期阻滞和侵袭力下降。PS作为膀胱癌多个异常通路上的关键酶，可能参与NMIBC向MIBC的恶性进展过程，这是我们的假设和研究的重点，也为PS可能作为一种新的晚期膀胱癌治疗靶点提供实验依据和理论基础。

Urothelial cell carcinoma of the bladder (UCB, bladder cancer) is the second most common malignancy of the urogenital systerm worldwide. Most UCBs are transitional cell carcinomas (TCCs) arising from the transitional epithelium that lines the bladder. Of these, more than 70% of new cases per annum are low-grade, papillary, non-muscle-invasive bladder cancer (NMIBC), despite local excision, they tend to recur in over 30% more or less of patients. However, mortality associated with UCB is mostly caused by a high-grade, non-papillary, muscle-invasive bladder cancer (MIBC), which accounts for up to 20-30% of new UCB cases. During the last three decades, no significant change was observed in UCB management, which may be attributed to a lack of breakthrough progress for UCB. Therefore, the application of special UCB-related molecular marks and new or refined technologies will help to determine UCB progress and provide new strategies for the treatment of advanced UCB cases. An aspartyl-protease complex in cell membrane, γ-secretase contains a key subunit presenilin (PS), which has two homologs, PS1 and PS2, both found in humans. They are the enzymic components that cleave more than 30 substrates, and produce as well as translocate intracellular domains (ICDs) of those substrates in nucleus. Most cleavages are transmembrane signals or proteins such as β-amyloid precursor protein (APP), Notch, VEFGR-1, IGF-1R, ErbB4, Cadherins, and CD44 etc. Studies suggested that PS/γ-secretase might be involved in various pathological processes and that inhibition of PS/γ-secretase could lead to cell cycle arrest, apoptosis, impaired ability of metastasis, and re-sensitization to chemotherapy in many cancer cells. So far, no study on the expression or functional role of PS in UCB has been reported, and more specific inhibitors of PS/γ-secretase are being explored and tested, which makes targeting PS/γ-secretase to be a real possibility. We investigate the expression levels of PS1 and PS2, a series of their substrates in human normal and malignant transitional urothelial samples and cells, as well as the effects of the PS/γ-secretase inhibitor DAPT on urothelial cells. Inhibition of PS/γ-secretase using the specific inhibitor DAPT elicited cell cycle arrest at G1/S stage and decreased the invasive ability of UCB cells (which might involve multiple pathways) in our pre-experiment. Moreover, our pre-experiment showed that the varied expression patterns of PS1 occured in the samples of non-muscle-invasive bladder cancer (NMIBC), which we speculated were associated to the evolution of NMIBC to muscle-invasive bladder cancer (MIBC) based on the primary results of our pre-experiment. The in toto role of the Presenilin in UCB should warrant wider studies and further in vivo experiments before it may serve as a potential molecullar mark or therapeutic target for UCB.