BUB1蛋白激活STAT3信号通路促进膀胱癌发生发展的机制研究

Bladder carcinoma is the most common malignancy in urinary system. Its etiology and pathogenesis are not very clear, it is difficult to implement effective prevention and treatment. It is showed that the development of bladder carcinoma is a multi stage process of multi genes and multi factors, and it is the result of the interaction between environment and genetic factors. Based on the previous screening studies of Genomics, the BUB1 as oncogene was identified and verified to be activated in bladder carcinoma tissues. We hypothesized that BUB1 protein of bladder urothelial cells phosphorylate STAT3 and form complex, complex move into nucleus and up-regulated SOX2 expression, modulating bladder epithelial stem / progenitor cell growth, resulting in the occurrence and development of bladder carcinoma. In this proposal, we are going to adopt the bladder epithelial-specific BUB1 knockout tumor mice and human bladder carcinoma specimen xenograft mice, using the laboratory methods and tools in experimental zoology, epigenetics and bioinformatics, to demonstrate that (a) BUB1 protein phosphorylate, active STAT3 and form complex; (b) complex move into nucleus and up-regulated SOX2 expression, which results in directing the bladder epithelial cell cancer stem/progenitor cells proliferation. Above all, we are going to testify that BUB1 is valuable to be treated as a target for bladder management.

膀胱肿瘤是最常见泌尿系统恶性肿瘤，目前病因及发病机制尚不很清楚，难以实施有效的预防和治疗。研究表明，膀胱肿瘤发生发展是多基因多因素参与的多阶段过程，是环境和遗传因素共同作用的结果，存在明显个体易感性。在前期多组学研究基础上，筛选验证了原癌基因BUB1在膀胱肿瘤组织中被激活。提出科学假说：膀胱上皮细胞中BUB1基因表达增高，BUB1蛋白磷酸化激活STAT3蛋白并与之形成复合体入核，复合体结合SOX2启动子区调节的SOX2表达上调，进而调节膀胱上皮干/祖细胞生长，导致膀胱肿瘤的发生发展。本项目拟采用膀胱上皮特异性BUB1基因敲除的膀胱肿瘤小鼠模型为研究对象。运用实验动物学和表观遗传学的研究手段，明确BUB1蛋白磷酸化激活STAT3的机制；BUB1与STAT3形成复合体正向调节SOX2信号系统进而调节膀胱肿瘤上皮干/祖细胞的生长。证实BUB1作为膀胱肿瘤药物治疗靶向分子的应用价值。

膀胱肿瘤是最常见泌尿系统恶性肿瘤，病因及发病机制尚不很清楚，难以实施有效的预防和治疗。研究表明，膀胱肿瘤发生发展是多基因多因素参与的多阶段过程，是环境和遗传因素共同作用的结果，存在明显个体易感性。在前期多组学研究基础上，筛选验证了原癌基因BUB1在膀胱肿瘤组织中被激活。结果发表在J Exp Clin Cancer Res、Cell Death Dis、Cancer Letters、Cell Death Discov等杂志上。在此基础上，提出一新的诊断治疗方案：膀胱癌病理组织活检染色BUB1蛋白指标增高诊断率，开发BUB1的抑制剂克服肿瘤干祖细胞生长，达到有效治疗前列腺癌的目的。初步体内体外实验证实：膀胱上皮细胞中BUB1基因表达增高，BUB1蛋白磷酸化激活STAT3蛋白并与之形成复合体入核，复合体结合SOX2启动子区调节的SOX2表达上调，进而调节膀胱上皮干/祖细胞生长，导致膀胱肿瘤的发生发展。 本项目是对以往治疗方案的优化与创新，更接近临床，将为膀胱癌治疗开辟一种新方法。