ETS-1 Induces Endothelial-Like Differentiation and Promotes Metastasis in Non-Small Cell Lung Cancer
ETS-1 Induces Endothelial-Like Differentiation and Promotes Metastasis in Non-Small Cell Lung Cancer
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ETS-1 诱导非小细胞肺癌内皮样分化并促进转移
DOI：
10.1159/000487874
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发表时间：
2018-02
影响因子：
--
通讯作者：
Zhenyu Li
中科院分区：
文献类型：
--
作者：
Xiaoshu Zhou;Rui Zhou;Hongxia Zhou;Qianwen Li;Jiaxin Hong;Rui Meng;Fang Zhu;Sheng Zhang;Xiaofang Dai;Gang Peng;Gang Wu;Zhenyu Li
背景/目的：最近发现了直接来源于肿瘤细胞的内皮样细胞。然而，其机制尚不清楚。ETS-1 （E26转化特异性-1）是内皮细胞生成和成熟的关键转录因子，据报道在几种癌症中过表达。在这里，我们揭示了ETS-1对NSCLC（非小细胞肺癌）细胞内皮样分化的新调控。方法：利用H2O2或慢病毒载体上调ETS-1在非小细胞肺癌细胞系中的表达。采用Western blot和免疫荧光法检测内皮表型，如血管性血友病因子（vWF）和ve -钙粘蛋白（VE-cadherin）。采用成管实验和吞噬活性实验评价ECs对NSCLC细胞的特异性。通过伤口愈合实验、transwell实验和异种移植肿瘤模型来确定ETS-1对转移的影响。为了探讨ETS-1在非小细胞肺癌发生和发展中的作用，我们采用免疫组化方法检测了ETS-1在非小细胞肺癌癌变组织和配对的邻近正常组织中的表达，并分析了ETS-1表达与临床病理参数以及患者生存率的关系。使用Kaplan Meier绘图数据库评估ETS-1在NSCLC中的预后价值。我们分析了ETS-1水平与微血管密度之间的关系，以确定它们在血管生成中的作用。结果：随着ETS-1的上调，NSCLC细胞中vWF和VE-cadherin的表达增加。此外，细胞采用了几种ec的特异性特征，包括增强的管形成能力和Dil-ac-LDL（乙酰化低密度脂蛋白）和凝集素的摄取。ETS-1的上调也促进了细胞的迁移、侵袭和粘附。此外，由ETS-1过表达细胞产生的异种移植小鼠有更多的肝转移。临床标本中，ETS-1在非小细胞肺癌癌组织中的表达明显高于癌旁非肿瘤组织，且与肿瘤大小、T分期、N分期及临床分期呈正相关。ETS-1高表达患者的OS（总生存期）和FP（首次进展）明显低于低表达患者。此外，ETS-1水平与MVD呈正相关。结论：综上所述，我们的数据表明ETS-1可以诱导肿瘤细胞向内皮样细胞分化，并进一步促进NSCLC的转移传播。
Background/Aims: Recently, endothelial-like cells originating directly from tumor cells have been revealed. However, the mechanism remains unclear. ETS-1 (E26 transformation specific-1), a key transcription factor in the generation and maturation of ECs (endothelial cells), has been reported to be overexpressed in several cancers. Here, we reveal novel regulation of the endothelial-like differentiation of NSCLC (non-small cell lung cancer) cells by ETS-1. Methods: We up-regulated the expression of ETS-1 in NSCLC cell lines by H2O2 or lentiviral vector. Endothelial phenotypes, such as vWF (von Willebrand factor) and VE-cadherin were examined by Western blot analysis and immunofluorescence assay. Tube formation assay and phagocytotic activity assay were performed to evaluate ECs’ specific features on NSCLC cells. The effect of ETS-1 on metastasis was determined by wound healing assays, transwell assays and a xenograft tumor model. To explore the role of ETS-1 in the initiation and progression of NSCLC, we examined ETS-1 levels in NSCLC cancerous tissues and paired adjacent normal tissues by immunohistochemstry and analyzed the relationship between ETS-1 levels and clinicopathological parameters, as well as patient survival. Kaplan Meier plotter database was used to assess the prognostic value of ETS-1 in NSCLC. The association between ETS-1 levels and MVD (microvessel density) was analyzed to determine their role in angiogenesis. Results: With ETS-1 up-regulation, the expression of vWF and VE-cadherin was increased in NSCLC cells. Additionally, cells adopted several ECs’ specific features, including enhanced tube formation ability and uptake of Dil-ac-LDL (acetylated low-density lipoprotein) and lectin. ETS-1 up-regulation also promoted cell migration, invasion and adhesion. In addition, xenograft mice arising from ETS-1 over-expressing cells had more liver metastases. In the clinical specimens, ETS-1 expression was significantly higher in NSCLC cancerous tissues than adjacent nontumorous tissues and positively associated with tumor size, T stage, N stage and clinical stage. Patients with high levels of ETS-1 expression had significantly poorer OS (overall survival) and FP (first progression) than those with low expression. Furthermore, there was a positive correlation between ETS-1 level and MVD. Conclusion: Collectively, our data reveal that ETS-1 can induce the differentiation of tumor cells into endothelial-like cells and further promote metastatic dissemination in NSCLC.
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影响因子：
2
作者：
F. Dunphy;B. Stack;J. Boyd;T. Dunleavy;H. Kim;C. Dunphy
通讯作者：
F. Dunphy;B. Stack;J. Boyd;T. Dunleavy;H. Kim;C. Dunphy
影响因子：
--
作者：
Findlay, Victoria J.;LaRue, Amanda C.;Turner, David P.;Watson, Patricia M.;Watson, Dennis K.
通讯作者：
Watson, Dennis K.
胚胎血管发育中的 ETS 转录因子。
影响因子：
9.8
作者：
Craig MP;Sumanas S
通讯作者：
Sumanas S
影响因子：
5.3
作者：
Qiao L;Liang N;Zhang J;Xie J;Liu F;Xu D;Yu X;Tian Y
通讯作者：
Tian Y
影响因子：
64.5
作者：
Ginsberg M;James D;Ding BS;Nolan D;Geng F;Butler JM;Schachterle W;Pulijaal VR;Mathew S;Chasen ST;Xiang J;Rosenwaks Z;Shido K;Elemento O;Rabbany SY;Rafii S
通讯作者：
Rafii S