Defects in Emerin-Nucleoskeleton Binding Disrupt Nuclear Structure and Promote Breast Cancer Cell Motility and Metastasis.
Defects in Emerin-Nucleoskeleton Binding Disrupt Nuclear Structure and Promote Breast Cancer Cell Motility and Metastasis.
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DOI：
10.1158/1541-7786.mcr-20-0413
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
Holaska JM
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文献类型：
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作者：
Liddane AG;McNamara CA;Campbell MC;Mercier I;Holaska JM
核膜蛋白在调节癌症的核大小和结构中发挥着重要作用。在许多癌症中发现核纤层蛋白表达的改变，其表达与更好的临床结果相关。细胞核是细胞中最大的细胞器，直径在10至20微米之间。核大小显着影响细胞迁移。预计核结构变化将通过调节癌细胞迁移来影响癌症转移。在这里，我们展示了艾默林调节侵袭性乳腺癌细胞的核结构以影响癌症转移。侵袭性乳腺癌细胞的 emerin 含量比对照细胞少 40-50%，这导致细胞核尺寸减小。侵袭性乳腺癌细胞中 GFP-emerin 的过度表达可挽救细胞核大小并抑制通过 3.0 和 8.0 μm 孔的迁移。突变分析表明，emerin 与核骨架蛋白的结合对于其核结构、迁移和侵袭的调节很重要。重要的是，在乳腺癌原位小鼠模型中，emerin 表达可抑制 91% 的肺转移。艾默林核骨架结合突变体未能抑制转移。这些结果支持了一个模型，即艾默林与核骨架结合调节核结构以影响转移。在该模型中，emerin 在转移转化中发挥核心作用，因为转化过程中 emerin 表达减少会导致细胞迁移、内渗和外渗增加所需的核结构缺陷。
Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 μm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40–50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 μm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation and extravasation.