Elp3在结直肠癌中调控Wnt/β-catenin信号通路的机制研究

Colorectal cancer is one of the most common malignant tumors worldwide. Although it has been intensively investigated in both clinic and laboratory, the diagnosis and treating regiment of colorectal cancer remain unsatisfied. Therefore, it is important to further investigate the etiology and metastasis of colorectal cancer. We previously demonstrated that Elp3 stabilizes Snail1 and in turn regulates the migration of neural crest cell, the procedure of metastasis of cancer cells is highly mimic neural crest migration. Furthermore, we showed that in colorectal cancer cell lines Elp3 binds and stabilizes β-catenin, the most salient component of Wnt signaling. Interestingly we also find the interaction answers to TGF-β signaling in colorectal cancer cell lines. Given Wnt/β-catenin and TGF-β signaling play essential roles in both initiation and progression of colorectal cancer, we speculate that Elp3 exerts its function on modulating Wnt/β-catenin and TGF-β signaling via biochemical regulation of β-catenin and/or Snail1. Herein, this proposal is primarily devoted to investigate the interrelation between Elp3, β-catenin and Snail1 whereby facilitates the Wnt/β-catenin and TGF-β signaling in colorectal cancer.

结直肠癌是消化道最常见的恶性肿瘤之一，虽然已有大量关于结直肠癌发病机制的研究工作被报道，但是临床上诊断和治疗的效果较差，所以关于其病因及转移机制的研究仍然显得尤为重要。我们的前期研究发现Elp3基因通过稳定Snail1蛋白调控与癌细胞高度类似的神经嵴细胞的迁移。进一步的研究发现Elp3结合并稳定Wnt信号的关键组分β-catenin蛋白，并在此过程中响应TGF-β信号。Wnt/β-catenin和TGF-β信号通路在结直肠癌的发生和发展中都发挥着关键的作用。在前期数据的基础上我们提出假设：在细胞系中探究Elp3稳定β-catenin以及Snail1调控结直肠癌关键信号通路Wnt/β-catenin和TGF-β，及其在结直肠癌发生和发展中扮演的重要角色。

Wnt/β-catenin信号通路能促进肿瘤细胞的增长和生存；它也可以调控许多与EMT相关的因子，包括Twist，ZEB1，Snail/Snail2等转录因子，这些转录因子又可以抑制细胞粘附蛋白E-cadherin，以促进细胞的迁移和侵袭。其中，Snail除了受到Wnt/β-catenin信号通路的调控以外，它自身也可以与β-catenin相互作用，并入核调控Wnt/β-catenin信号通路，激活其下游靶基因的表达。本项目主要研究内容：1). 通过结直肠癌细胞系和非洲爪蛙胚胎发现Elp3对Snail的调控依赖于其两个功能性结构域；2). 通过稳定敲低/过表达Elp3的细胞系研究发现，Elp3可以通过调节Wnt/β-catenin信号通路而介导细胞的增殖/周期和迁移/侵袭；3). 进一步的研究发现敲低Elp3能促进SW480细胞的迁移和侵袭（体内/体外系统），这主要通过其对E-cadherin的蛋白稳定性、蛋白周期循环调控进而引起了对细胞内钙离子浓度产生的影响而调控的。我们的研究结果揭示了Elp3对Wnt/β-catenin信号通路几个关键蛋白Snail，β-catenin，E-cadherin稳定性的调控，建立了相对完善的Elp3-Wnt/β-catenin(Snail/β-catenin)-E-cadherin的工作网络，有助于结直肠癌分子调控网络的完善和临床恶性程度的诊疗标准的建立。