Overexpression of the VRK1 kinase, which is associated with breast cancer, induces a mesenchymal to epithelial transition in mammary epithelial cells.
Overexpression of the VRK1 kinase, which is associated with breast cancer, induces a mesenchymal to epithelial transition in mammary epithelial cells.
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DOI：
10.1371/journal.pone.0203397
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Traktman P
中科院分区：
文献类型：
--
作者：
Mon AM;MacKinnon AC Jr;Traktman P
牛痘相关激酶1（VRK 1）是一种促增殖核激酶。移植有VRK 1耗尽的MDA-MB-231乳腺癌细胞的小鼠显示出比对照组更少的远端转移，这表明VRK 1可能在细胞迁移、侵袭和/或定殖中起作用。在本文所述的工作中，我们研究了VRK 1过表达对人乳腺上皮细胞的影响。在2D培养中，VRK 1过表达减少了细胞迁移和侵袭，并损害了细胞扩散和细胞骨架重排的迁移相关过程。VRK 1过表达细胞显示间充质标志物波形蛋白的积累减少，上皮标志物E-钙粘蛋白和密蛋白-1的积累增加。VRK 1过表达还导致转录抑制因子snail、slug和twist 1水平降低。累积起来，这些数据表明VRK 1过表达增强了MCF 10a和MDA-MB-231细胞的上皮特性。我们进一步研究了VRK 1对3D基质胶培养中MCF 10a细胞上皮特性的影响，其中细胞增殖并形成成熟为中空球形腺泡的上皮片。VRK 1过表达显著加速细胞增殖的初始阶段，导致更大的腺泡，但仍分化和成熟。我们对人类肿瘤组织微阵列（TMAs）的分析显示，VRK 1蛋白水平在淋巴结转移中高于患者匹配的乳腺肿瘤。使用公共数据库，我们确定VRK 1是浸润性乳腺癌多种亚型中前10%的过度表达转录物，并且VRK 1高水平表达与无复发生存率降低相关。总之，VRK 1的过表达，通过调节转录抑制因子snail，slug和twist 1，可以促进细胞培养中的间充质-上皮转化（MET）。VRK 1介导的MET可能有助于转移性乳腺癌细胞在远端部位的定植，从而为VRK 1过表达与乳腺恶性肿瘤的频繁相关性以及VRK 1过表达与不良临床结局之间的相关性提供了一些见解。
Vaccinia-related kinase 1 (VRK1) is a pro-proliferative nuclear kinase. Mice engrafted with VRK1-depleted MDA-MB-231 breast cancer cells have been shown to develop fewer distal metastases than controls, suggesting VRK1 might play a role in cell migration, invasion, and/or colonization. In work described herein, we investigated the impact of VRK1 overexpression on human mammary epithelial cells. In 2D culture, VRK1 overexpression diminishes cell migration and invasion and impairs the migration-associated processes of cell spreading and cytoskeletal rearrangement. VRK1-overexpressing cells show reduced accumulation of the mesenchymal marker vimentin and increased accumulation of the epithelial markers E-cadherin and claudin-1. VRK1 overexpression also leads to reduced levels of the transcriptional repressors snail, slug, and twist1. Cumulatively, these data indicate that VRK1 overexpression augments the epithelial properties of both MCF10a and MDA-MB-231 cells. We further studied the impact of VRK1 on the epithelial properties of MCF10a cells in 3D matrigel culture, in which cells proliferate and form epithelial sheets that mature into hollow spherical acini. VRK1 overexpression significantly accelerates the initial stages of cell proliferation, leading to larger acini that nevertheless differentiate and mature. Our analysis of human tumor tissue microarrays (TMAs) revealed that VRK1 protein levels are higher in lymph node metastases than in patient-matched mammary tumors. Using public databases, we determined that VRK1 is among the top 10% of overexpressed transcripts in multiple subtypes of invasive breast cancer, and that high levels of VRK1 expression are correlated with decreased relapse-free survival. In sum, overexpression of VRK1, by regulating the transcription repressors snail, slug, and twist1, can promote a mesenchymal-to-epithelial transition (MET) in cell culture. VRK1-mediated MET might facilitate the colonization of distal sites by metastatic breast cancer cells, providing some insight into the frequent association of VRK1 overexpression with breast malignancies and the correlation between VRK1 overexpression and poor clinical outcome.
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影响因子：
--
作者：
Lee N;Kwon JH;Kim YB;Kim SH;Park SJ;Xu W;Jung HY;Kim KT;Wang HJ;Choi KY
通讯作者：
Choi KY
影响因子：
3.7
作者：
Choi YH;Park CH;Kim W;Ling H;Kang A;Chang MW;Im SK;Jeong HW;Kong YY;Kim KT
通讯作者：
Kim KT
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
5.3
作者：
Kang, Tae-Hong;Park, Do-Young;Kim, Kyong-Tai
通讯作者：
Kim, Kyong-Tai