The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer
The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer
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Wnt/β-连环蛋白/VASP 正反馈环驱动乳腺癌细胞增殖和迁移
DOI：
10.1038/s41388-019-1145-3
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发表时间：
2020-03-01
期刊：
影响因子：
8
通讯作者：
Wei, Lei
中科院分区：
文献类型：
--
作者：
Li, Kai;Zhang, Jingwei;Wei, Lei
以往的研究表明，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，我们首次发现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。我们确定VASP是Wnt/beta-catenin信号通路的靶基因，激活Wnt/beta-catenin信号通路可显著上调VASP蛋白的表达，而上调的VASP蛋白又可促进beta-catenin和DVL 3蛋白向细胞核转位。在细胞核中，VASP、DVL 3、beta-catenin和TCF 4可形成VASP/DVL 3/beta-catenin/TCF 4蛋白复合物，激活Wnt/beta-catenin信号通路，促进靶基因VASP、c-myc和cyclin D1的表达。因此，我们的研究揭示了乳腺癌中存在Wnt/beta-catenin/VASP恶性正反馈环，促进乳腺癌细胞的增殖和迁移，打破这一正反馈环可能为乳腺癌治疗提供新的策略。
Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/beta-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/beta-catenin signaling pathway, and activation of Wnt/beta-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of beta-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, beta-catenin, and TCF4 can form VASP/DVL3/beta-catenin/TCF4 protein complex, activating Wnt/beta-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc, and cyclin D1. Thus, our study reveals that there is a Wnt/beta-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.