Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis.
Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis.
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DOI：
10.1091/mbc.e10-09-0790
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发表时间：
2011-02-01
影响因子：
3.3
通讯作者：
Turner CE
中科院分区：
文献类型：
--
作者：
Deakin NO;Turner CE
这项研究揭示了黏着斑蛋白桩蛋白和Hic-5在调节乳腺癌侵袭策略和转移中的新作用。桩蛋白的消耗促进了超间充质表型，同时失调3D粘附动力学。相反，Hic-5的RNAi诱导具有失调的RhoA/pMLC信号传导的超阿米巴样表型。单个转移性肿瘤细胞在组织侵袭期间表现出两种可相互转换的细胞运动模式，其被分类为间充质或变形虫。侵袭性乳腺癌细胞调节这种迁移可塑性的分子机制尚未完全阐明。在这里，我们表明，粘着斑适配器蛋白，桩蛋白，和密切相关的Hic-5有不同的和独特的作用，在乳腺癌细胞肺转移的调节，通过调节细胞形态和细胞侵袭，通过三维细胞外基质（3D ECM）。通过RNA干扰去除桩蛋白的细胞显示出高度伸长的间充质形态，而Hic-5敲低诱导了两个细胞群体表现出降低的可塑性、迁移持久性和通过3D ECM环境的速度的变形虫表型。在评估相关的信号通路，我们确定，Rac 1活性增加，在细胞中没有桩蛋白，而Hic-5沉默导致RhoA活性升高和相关的Rho激酶诱导的非肌肉肌球蛋白II活性。HIC-5是必不可少的粘附形成在3D ECM，粘附动力学和寿命的分析确定桩蛋白作为一个关键的调节器的3D粘附组装，稳定和拆卸。
This study reveals novel roles for the focal adhesion proteins paxillin and Hic-5 in regulating breast cancer invasion strategies and metastasis. Depletion of paxillin promotes a hypermesenchymal phenotype while dysregulating 3D adhesion dynamics. In contrast, RNAi of Hic-5 induces a hyperamoeboid phenotype with dysregulated RhoA/pMLC signaling. Individual metastatic tumor cells exhibit two interconvertible modes of cell motility during tissue invasion that are classified as either mesenchymal or amoeboid. The molecular mechanisms by which invasive breast cancer cells regulate this migratory plasticity have yet to be fully elucidated. Herein we show that the focal adhesion adaptor protein, paxillin, and the closely related Hic-5 have distinct and unique roles in the regulation of breast cancer cell lung metastasis by modulating cell morphology and cell invasion through three-dimensional extracellular matrices (3D ECMs). Cells depleted of paxillin by RNA interference displayed a highly elongated mesenchymal morphology, whereas Hic-5 knockdown induced an amoeboid phenotype with both cell populations exhibiting reduced plasticity, migration persistence, and velocity through 3D ECM environments. In evaluating associated signaling pathways, we determined that Rac1 activity was increased in cells devoid of paxillin whereas Hic-5 silencing resulted in elevated RhoA activity and associated Rho kinase–induced nonmuscle myosin II activity. Hic-5 was essential for adhesion formation in 3D ECMs, and analysis of adhesion dynamics and lifetime identified paxillin as a key regulator of 3D adhesion assembly, stabilization, and disassembly.