Circ-BNC2通过编码蛋白调控膀胱癌转移的机制研究

Circular RNA (CircRNA) plays an important role in the metastasis of bladder cancer. However, the detail molecular mechanism has not yet been elucidated. In our previous study, we firslyt discovered a novel tumor suppressor CircRNA that encoded a protein associated with bladder cancer metastasis and named it Circ-BNC2. Our further studies suggested that Circ-BNC2 encoded the protein Circ-BNC2-681aa, and the metastasis of bladder cancer was promoted if silencing of this gene. To obtain convincing evidence of Circ-BNC2 silencing leading to bladder cancer metastasis, this study intends to use high-throughput sequencing, in vitro and in vivo model validation techniques to identify Circ-BNC2-681aa protein can regulate downstream metastasis-related molecules. Next we will confirm this downstream target through salvage experiments. This project will focus on the scientific hypothesis that Circ-BNC2 silencing leads to the down-regulation of Circ-BNC2-681aa expression and the abnormal expression of downstream metastasis-associated geens, which promotes the invasion and metastasis of bladder cancer cells. We will investigate the detail functional mechanism of Circ-BNC2, which may reveal the essence of bladder cancer metastasis caused, to provide a scientific basis for its establishment as a marker for predicting bladder cancer metastasis and a new potential target for treatment.

环状RNA（CircRNA）在膀胱癌转移中起重要作用，但其中的具体分子机制尚未阐明。我们前期研究首次发现一个与膀胱癌转移相关的可编码蛋白的抑癌CircRNA，并命名为Circ-BNC2，进一步研究提示Circ-BNC2可编码蛋白Circ-BNC2-681aa，该基因的表达沉默促进了膀胱癌的转移。本课题拟进一步采用高通量测序和体内外模型验证等技术，鉴定Circ-BNC2-681aa蛋白调控下游转移相关分子，获得Circ-BNC2沉默导致膀胱癌转移的可靠证据。本项目将紧紧围绕“Circ-BNC2沉默导致Circ-BNC2-681aa蛋白表达下调和下游转移相关基因的表达异常，促进膀胱癌细胞侵袭和转移”的科学假说，从Circ-BNC2的全新调控机制入手，揭示其表达沉默导致膀胱癌转移的本质，为确立其作为预测膀胱癌转移标记物和治疗新靶点提供科学依据。

淋巴转移是膀胱癌患者死亡的主要原因。探究膀胱癌淋巴转移的机制并寻找早期诊断标记物和治疗靶标成为膀胱癌相关研究的重点内容。在本研究中，我们发现Circ-BNC2在淋巴转移阳性膀胱癌组织中低表达，在膀胱癌细胞中过表达或敲低Circ-BNC2后，膀胱癌细胞淋巴转移分别得到抑制或增强。在机制上，Circ-BNC2通过编码Circ-BNC2-681aa与LEF1竞争性结合，抑制LEF1结合到下游靶基因启动子区域，从而抑制EMT，抑制膀胱癌细胞转移。综上所述，Circ-BNC2通过编码一种新型淋巴转移相关蛋白发挥作用，抑制膀胱癌淋巴转移。这为CircRNA通过编码蛋白调控淋巴转移的机制提供了新的思路，同时为靶向CircRNA治疗淋巴转移提供新的理论依据。