ERCC6L调控SEPT2促进膀胱癌转移的作用和分子机制研究

研究膀胱癌（UCB）转移机制是改善UCB疗效关键。我们在前期预实验中筛选和鉴定了一个新的候选癌基因ERCC6L，其表达上调与UCB预后和UCB细胞侵袭能力密切相关，其机制可能是ERCC6L上调Rho GTPase通路关键调节蛋白SEPT2，C-MYC可能是介导ERCC6L调控SEPT2转录的重要因子。但ERCC6L在UCB转移中的作用和上调SEPT2的机制尚不清楚，本项目拟首先探讨ERCC6L对UCB细胞转移生物学行为的影响，应用ChIP和荧光素酶报告基因等实验，明确ERCC6L调控SEPT2是否依赖于转录因子C-MYC，进一步，验证ERCC6L和C-MYC是否存在物理性结合，同时探讨ERCC6L过表达是否促进C-MYC与SEPT2启动子结合，使SEPT2表达上调。最后，综合分析并确定ERCC6L调控SEPT2促进UCB转移的分子机制，并评估其临床应用潜力，旨在为UCB带来新的靶点。

The study of metastatic mechanism of urothelial carcinoma of the bladder（UCB）is the key to improve the overall survival rate. In our preliminary study we characterized a candidate oncogene, ERCC6L, which was found to have a clinicopathologic/prognostic significance in UCB patients and involved in tumor aggressiveness. SEPT2, a regulator of Rho GTPase signaling pathway, was demonstrated as a target downstream gene regulated by ERCC6L in UCB. However, its oncogenic role in UCB aggressiveness and underlying molecular mechanisms is unclear. In the present study, we investigated whether expression of ERCC6L in UCB cells is important for cell invasive and/or metastatic capacity. We then plan to confirm whether overexpression of ERCC6L caused a sizeable increase of C-MYC binding at the SEPT2 promoter leading to increased SEPT2 transcription. Moreover, up-regulation of SEPT2 by ERCC6L in UCB cells is dependent on C-MYC. Such observations are suggestive of the potential use of ERCC6L as a potential therapeutic tool for UCB.