基于Wnt/β-catenin信号通路的VASP促进乳腺癌细胞增殖和迁移的机制研究

The incidence of breast cancer ranked first in female tumors, but the generation and development of breast cancer is still an unclear biological process. Our previous study revealed that higher VASP expression level in breast cancer tissue was correlated with lower disease free percent survival in breast cancer patients. In addition, overexpression of VASP could promote the proliferation and migration of breast cancer cells, significantly elevate the protein expression level of VASP and β-catenin in nucleus, and upregulate the expression level of c-myc, which is a typical target gene of Wnt/β-catenin signaling pathway. Moreover, VASP could bind to the β-catenin/TCF4 transcription-regulation complex via Dvl3 in the nucleus and increase the activity of β-catenin/TCF4 transcription-regulation complex. By overexpressing β-catenin and/or knocking down VASP inside cells, it is shown that the transcriptional activation function of the β-catenin/TCF4 transcription-regulation complex requires assistance of VASP protein. Therefore, this project intends to investigate the role of VASP in activating the transcription of the target genes in Wnt/β-catenin signaling pathway as a coactivator of transcription-regulation complex during promotion the proliferation and migration of breast cancer cells, which will be benefit for better understanding a novel signaling pathway in breast cancer development.

乳腺癌发病率位列女性肿瘤首位，但其发生发展机制仍不太明确。我们前期研究发现，VASP在乳腺癌组织中的表达水平明显增高，与患者无病生存率呈负相关。并且VASP过表达促进乳腺癌细胞增殖和迁移，更为重要的是VASP和β-catenin蛋白表达水平在细胞核中明显增高，Wnt/β-catenin信号通路下游靶基因c-myc表达上调，并且VASP在细胞核中可能通过Dvl3与β-catenin/TCF4转录调控复合物结合，并增加其转录活性。通过过表达β-catenin和/或干扰VASP策略，结果显示β-catenin/TCF4转录调控复合物的转录激活功能的发挥需要VASP蛋白的辅助。因此，本项目拟阐释VASP作为β-catenin/TCF4转录调控复合物的共激活因子，增强Wnt/β-catenin信号通路靶基因的转录，从而促进乳腺癌细胞的增殖和迁移。项目将从信号通路角度，为研究乳腺癌发生发展提供新思路。

肿瘤流行病学统计显示乳腺发病率和死亡率在女性肿瘤中排名第一，全球每年新增大约170万乳腺癌病例。乳腺癌的发病率逐年增加，发病年龄呈年轻化趋势。尽管乳腺癌的综合治疗措施不断改善，但乳腺癌仍是导致女性死亡的重要原因之一。以往研究表明，VASP的主要功能是调节细胞骨架，在促进肿瘤细胞转移中发挥重要作用。在这项研究中，我们首先揭示了 VASP 位于乳腺癌细胞的细胞核中，并阐明了 Wnt/β-catenin/VASP 正反馈回路。我们发现VASP是Wnt/β-catenin信号通路的靶基因，Wnt/β-catenin信号通路的激活可以显着上调VASP蛋白表达，而上调的VASP蛋白反过来又可以促进β-catenin和DVL3蛋白的易位。进入细胞核。在细胞核内，VASP、DVL3、β-catenin、TCF4可形成VASP/DVL3/β-catenin/TCF4蛋白复合物，激活Wnt/β-catenin信号通路，促进靶基因VASP、c-myc和cyclin D1。因此，我们的研究揭示了乳腺癌中存在一个Wnt/β-catenin/VASP恶性正反馈回路，促进了乳腺癌细胞的增殖和迁移，打破这一正反馈回路可能为乳腺癌治疗提供新的策略。