Nuclear dysmorphia, characterized by crumpled or lobulated polymorphic nuclear shapes, has been used as an index for the malignant grades of certain cancers. The expression of vimentin, a type-III intermediate filament protein, is a hallmark of the epithelial-to-mesenchymal transition. However, it remains unclear whether vimentin is involved in cancer cell nuclear dysmorphia. In this study, we found that vimentin intermediate filaments (VIFs) frequently accumulated at the concave of dysmorphic nucleus in breast cancer MDA-MB-231 cells. Depletion of vimentin apparently restored the nuclear shape of the cells, which was devastated by re-expression of vimentin, but not its assembly-defective Y117D mutant. Depletion of plectin, a cytoskeletal linker, partially prevented the perinuclear accumulation of VIFs and concomitantly restored the nuclear shape of the cells. In addition, depletion of vimentin in lung cancer A549 cells largely prevented nuclear dysmorphia during the epithelial-to-mesenchymal transition induced by TGFβ. Moreover, we found that VIF-mediated nuclear dysmorphia led to defects in DNA repair. Together, our results unveil a novel role of VIFs in cancer cell nuclear dysmorphia, which is associated with genome instability.

中文翻译：

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波形蛋白中间丝的核周组装诱导癌细胞核畸形


核畸形，以皱缩或分叶状的多态性核形状为特征，已被用作某些癌症恶性等级的指标。波形蛋白是一种 III 型中间丝蛋白，其表达是上皮到间充质转变的标志。然而，目前尚不清楚波形蛋白是否与癌细胞核畸形有关。在这项研究中，我们发现波形蛋白中间丝 （VIFs） 经常积聚在乳腺癌 MDA-MB-231 细胞畸形核的凹处。波形蛋白的耗竭显然恢复了细胞的核形状，而细胞的核形状被波形蛋白的重新表达破坏，但其组装缺陷型 Y117D 突变体没有被破坏。细胞骨架接头 plectin 的耗竭部分阻止了 VIF 的核周积累，并同时恢复了细胞的核形状。此外，肺癌 A549 细胞中波形蛋白的耗竭在很大程度上阻止了 TGFβ 诱导的上皮到间充质转化过程中的核畸形。此外，我们发现 VIF 介导的核畸形导致 DNA 修复缺陷。总之，我们的结果揭示了 VIF 在癌细胞核畸形中的新作用，这与基因组不稳定性有关。