Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation.
Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation.
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DOI：
10.18632/oncotarget.3862
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发表时间：
2015-06-30
期刊：
影响因子：
--
通讯作者：
Wang YK
中科院分区：
文献类型：
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作者：
Liu CY;Lin HH;Tang MJ;Wang YK
细胞骨架组织和局部黏附转换的调节与肿瘤的发生和上皮-间充质转化(EMT)密切相关，后者伴随着上皮标志物的丢失和间质标志物(如波形蛋白)的获得。临床微阵列结果表明，化疗后Vimentin mRNA水平的升高与乳腺癌患者的预后不良有关。我们假设波形蛋白介导了细胞骨架的重组，以维持EMT癌细胞的机械完整性。通过基因敲除策略，结果显示，在MDA-MB 231细胞中，细胞增殖减少，伤口愈合受损，失去定向迁移，并增加了大量的膜延伸。波形蛋白的缺失还导致细胞骨架的重组和局灶性粘连的减少，这导致细胞僵硬和收缩力降低，从而导致机械强度下降。此外，在MCF7细胞中过表达波形蛋白增加了细胞的硬度，增加了细胞的运动性和定向迁移，重定向了微管的极性，并由于β1整合素的增加和连接蛋白E钙粘附素的丢失而增加了EMT表型。与EMT相关的转录因子slug也是由波形蛋白介导的。目前的研究表明，波形蛋白通过调节EMT癌细胞的细胞骨架结构和细胞力生成的平衡来维持细胞内的机械动态平衡。
Modulations of cytoskeletal organization and focal adhesion turnover correlate to tumorigenesis and epithelial-mesenchymal transition (EMT), the latter process accompanied by the loss of epithelial markers and the gain of mesenchymal markers (e.g., vimentin). Clinical microarray results demonstrated that increased levels of vimentin mRNA after chemotherapy correlated to a poor prognosis of breast cancer patients. We hypothesized that vimentin mediated the reorganization of cytoskeletons to maintain the mechanical integrity in EMT cancer cells. By using knockdown strategy, the results showed reduced cell proliferation, impaired wound healing, loss of directional migration, and increased large membrane extension in MDA-MB 231 cells. Vimentin depletion also induced reorganization of cytoskeletons and reduced focal adhesions, which resulted in impaired mechanical strength because of reduced cell stiffness and contractile force. In addition, overexpressing vimentin in MCF7 cells increased cell stiffness, elevated cell motility and directional migration, reoriented microtubule polarity, and increased EMT phenotypes due to the increased β1-integrin and the loss of junction protein E-cadherin. The EMT-related transcription factor slug was also mediated by vimentin. The current study demonstrated that vimentin serves as a regulator to maintain intracellular mechanical homeostasis by mediating cytoskeleton architecture and the balance of cell force generation in EMT cancer cells.