Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients.
Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients.
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DOI：
10.1371/journal.pone.0172559
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Vaidya M
中科院分区：
文献类型：
--
作者：
Dmello C;Sawant S;Alam H;Gangadaran P;Mogre S;Tiwari R;D'Souza Z;Narkar M;Thorat R;Patil K;Chaukar D;Kane S;Vaidya M
波形蛋白是一种中间丝蛋白，主要在间充质来源的细胞中表达，尽管其异常表达见于许多上皮间充质转化的癌中。在癌症中，波形蛋白表达与从更分化的上皮表型到去分化状态的转变相关。鉴于角蛋白（Ks）作为上皮细胞分化调节因子的作用，了解波形蛋白是否通过角蛋白的重编程调节转化细胞的分化是很重要的。为了解决这个问题，波形蛋白在口腔癌衍生细胞中稳定下调。此外，在高盐角蛋白提取后进行整体角蛋白分析。在波形蛋白下调后，发现K5/K14对在蛋白和mRNA水平上均显著下调。我们实验室之前的研究表明K5/K14对在鳞状上皮细胞的增殖和分化中发挥作用。波形蛋白耗尽的细胞表现出分化状态的增加，其特征在于分化特异性标志物K1、外皮蛋白、聚丝蛋白和兜甲蛋白的水平增加，而其增殖状态保持不变。用在波形蛋白敲低背景中过表达的K5/K14对进行的挽救实验导致分化状态降低。Δ Np 63是波形蛋白的间接靶点之一，通过波形蛋白调节K5/K14的表达水平。此外，免疫组化显示高波形蛋白-K14表达与口腔癌患者的复发/生存不良之间存在显著相关性。因此，总之，波形蛋白通过调节K5/K14表达来调节分化开关。此外，波形蛋白-K14一起可能被证明是新的标记物，为人类口腔癌的复发。
Vimentin is an intermediate filament protein, predominantly expressed in cells of mesenchymal origin, although its aberrant expression is seen in many carcinomas during epithelial mesenchymal transition. In cancer, vimentin expression is associated with the transition from a more differentiated epithelial phenotype to a dedifferentiated state. In view of the perceived role of keratins (Ks) as regulators of differentiation in epithelia, it was important to understand whether vimentin modulates differentiation through the reprogramming of keratins, in transformed cells. To address this, vimentin was stably downregulated in oral cancer derived cells. Further, global keratin profiling was performed after high salt keratin extraction. K5/K14 pair was found to be significantly downregulated, both at protein and mRNA levels upon vimentin downregulation. The previous study from our laboratory has shown a role of the K5/K14 pair in proliferation and differentiation of squamous epithelial cells. Vimentin depleted cells showed an increase in the differentiation state, marked by an increase in the levels of differentiation specific markers K1, involucrin, filaggrin and loricrin while its proliferation status remained unchanged. Rescue experiments with the K5/K14 pair overexpressed in vimentin knockdown background resulted in decreased differentiation state. ΔNp63 emerged as one of the indirect targets of vimentin, through which it modulates the expression levels of K5/K14. Further, immunohistochemistry showed a significant correlation between high vimentin-K14 expression and recurrence/poor survival in oral cancer patients. Thus, in conclusion, vimentin regulates the differentiation switch via modulation of K5/K14 expression. Moreover, vimentin-K14 together may prove to be the novel markers for the prognostication of human oral cancer.