CUGBP1调节细胞间粘附促进肠癌循环肿瘤细胞簇（CTM）形成及转移的机制

Metastasis is the main difficulty among colorectal cancer clinical therapy. In our previous work of microarray in colorectal cancer, we identified a molecular candidate, CUGBP1, played an important role in process of colorectal cancer metastasis. We found a positive relationship between CUGBP1 expression level and the migration of colon cancer cell line. Dispite we demonstrated decreasing activity of MMPs in CUGBP1 silencing colon cancer cell, some cell adhesion moleculethe did not meet the phenotype of cancer cells migrating, which confused us. In further study, we figured out that CUGBP1 enhanced the stability of plakoglobin, thus promoted the formation of circulating tumor cell clusters, which is regulate the cancer distant metastasis. We will simultaneously elucidate the function of CUGBP1 in regulation of circulating tumor cell clusters and metastasis promotion through clinical tissue, cell line, animal model and explore the downstream signaling pathway of CUGBP1 by identifying the RNA and proteins which can interact with this molecule. Furthermore, through the experiment to explore that CUGBP1 regulation the transcriptional or protein level expression of GSK-3beta to realize the regulation of plakoglobin.It is proposed that CUGBP1 can be used as a new theraputic target for the metastasis of colorectal cancer via our work.

大肠癌肝转移是影响预后的主要难点。申请人收集肠癌转移灶与原发灶组织，通过基因芯片及定量PCR发现CUGBP1在大肠癌转移灶中特异性高表达，并证实CUGBP1能够促进大肠癌细胞发生增殖和迁移。同时发现其能够促进基质金属蛋白酶的表达，但是对粘附分子E-cadherin（不受影响）和盘状球蛋白plakoglobin（CUGBP1促进其表达）的表达与预期相反。申请人的初步实验认为该现象的机制是通过促进循环肿瘤细胞簇形成实现的，深入机制有待解释。本项目拟在此基础上，阐明CUGBP1调节循环肿瘤细胞簇形成的具体作用机制，重点关注plakoglobin调节的信号通路，并通过实验进一步探讨CUGBP1调节GSK-3β的转录/表达从而实现对plakoglobin蛋白水平调节。最终在大规模组织样本中验证CUGBP1、plakoglobin等在肠癌转移组织中的表达水平高低与肠癌患者预后的相关性，揭示其临床意义。

大肠癌肝转移是影响预后的主要难点。本项目在前期研究结果（1）CUGBP1在大肠癌转移灶中特异性高表达，（2）CUGBP1能够促进大肠癌细胞发生增殖和迁移，的基础上，在细胞、动物以及组织样本层面上进行深入研究，证实CUGBP1功能的发挥通过调控plakoglobin基因的表达而实现，并且这一过程依赖于GSK-3β的表达，组织样本检测明确CUGBP1与plakoglobin的表达呈正相关，提示CUGBP1和plakoglobin是潜在的大肠癌治疗靶点。本项目开展过程中发现，细胞增殖和蛋白翻译相关的信号通路分子可能也是CUGBP1的下游调控因子，提示除了GSK-3β和plakoglobin以外，还存在其它的因子可以介导CUGBP1的功能，值得后续进一步深入研究。