UT-B基因敲除小鼠膀胱癌易感性与分子机制研究

Urea transporter UT-B is a kind of channel protein facilitated urea transport along concentration gradient and expresses in red blood cells, kidney, ureter, bladder, testis and heart. Epidemiological studies found that bladder cancer occurrence and development was closely related with UT-B gene (SLC14A1) variation. UT-B is highly expressed in transitional cells of bladder cancer, while transitional cells located in bladder are over proliferation accompanied with insufficient apoptosis in UT-B knockout mouse. Excessive cell proliferation even malignant transform involves multiple cellular signal transduction process abnormalities and is closely related with oxidative stress. UT-B deletion is a critical factor inducing endogenous mitochondrial oxidative stress. The purpose of this project is to observe the role of oxidative stress in bladder cancer occurrence and development through bladder cancer model of UT-B knockout mouse in situ. The main contents of this project include (1) to copy orthotopic bladder cancer model in UT-B knockout mouse (2) to observe the effect of coenzyme Q10 on bladder cancer occurrence and development (3) to explore the molecular mechanism between mitochondrial oxidative stress and bladder cancer. Then explore the susceptibility to bladder cancer of UT-B knockout from mitochondrial oxidative stress, abnormal cell signal transduction et al and carry out experimental treatment with AQ10. The research findings can provide a new strategy for bladder cancer in clinic.

尿素通道蛋白UT-B在红细胞、肾脏、输尿管、膀胱、睾丸和心脏等多个组织表达，是介导尿素顺浓度梯度跨膜转运的膜蛋白。流行病学研究发现：膀胱癌的发生、发展与UT-B基因（SLC14A1）变异密切相关。UT-B在膀胱移行上皮高表达，而UT-B基因敲除小鼠膀胱移行上皮细胞过度增殖伴凋亡不足。细胞增殖与凋亡失衡涉及多个细胞信号转导过程异常，与氧化应激关系密切。UT-B缺失是造成内源性线粒体氧化应激的关键因素。本项目拟利用UT-B基因敲除小鼠诱导原位膀胱癌模型，对比观察氧化应激在膀胱癌发生发展中的作用。研究内容主要包括：（1）复制UT-B基因敲除鼠原位膀胱癌模型；(2) 观察辅酶Q10对膀胱癌发生、发展的影响；(3) 膀胱癌发生与线粒体氧化应激关系的分子机制。从细胞恶变与线粒体氧化应激、细胞信号转导异常等角度，探讨UT-B缺失易患膀胱癌的相关机制，并进行实验治疗，为临床制定膀胱癌防治策略提供新依据。

尿素通道蛋白UT-B在红细胞、肾脏、输尿管、膀胱、睾丸和心脏等多个组织表达，是介导尿素顺浓度梯度跨膜转运的膜蛋白。UT-B在膀胱移行上皮高表达，而UT-B基因敲除小鼠膀胱移行上皮细胞过度增殖伴凋亡不足。本项目利用UT-B基因敲除小鼠诱导原位膀胱癌模型，观察氧化应激在膀胱癌发生发展中的作用，同时观察UT-B蛋白在人膀胱癌组织的表达变化及IL-17家族在膀胱癌中表达变化的意义。本项目的主要研究内容包括：（1）复制UT-B基因敲除鼠原位膀胱癌模型；(2) 观察辅酶Q10对膀胱癌发生、发展的影响并分析相关机制；（3）UT-B蛋白在人膀胱癌组织中的表达；（4）IL-17家族成员在膀胱癌组织中的表达变化及意义等。主要结果有：（1）明确了UT-B在野生型小鼠和UT-B基因敲除鼠在泌尿系统表达差异；（2）明确了UT-B基因敲除小鼠基因变化（3）成功复制了膀胱原位癌模型，（4）辅酶Q10对膀胱癌的发生发展具有抑制效应（5）IL-17家族、炎细胞浸润和结构细胞变化对膀胱癌发生发展的影响。本项目从细胞恶变与线粒体氧化应激、细胞信号转导异常、IL-17家族表达变化等方面探讨UT-B缺失易患膀胱癌的相关机制，为临床制定膀胱癌防治策略提供新依据。