Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells
Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells
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DOI：
10.1016/j.tiv.2016.04.012
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发表时间：
2016-09-01
影响因子：
3.2
通讯作者：
Mollerup, Steen
中科院分区：
文献类型：
--
作者：
Bersaas, Audun;Arnoldussen, Yke Jildouw;Mollerup, Steen
肺癌主要是一种预后不良的环境引起的疾病。采用人支气管上皮细胞（HBEC）体外转化模型，研究烟草烟雾致癌物对上皮-间质转化（EMT）和叉头盒转录因子FOXA 1和FOXA 2的长期影响。将CDK 4和hTERT永生化的HBEC 2和HBEC 12细胞系每周暴露于香烟烟雾冷凝物（CSC）、苯并[a]芘或甲基亚硝基脲。暴露12周后，从软琼脂集落建立转化细胞系。所有暴露均转化了HBEC 12，而仅CSC转化了HBEC 2。未转化的HBEC 2显示出很小的侵袭能力，而转化的细胞系在基质胶划痕试验中完全关闭了差距。CDH 1在所有转化细胞系中下调。相比之下，CDH 2在HBEC 2和HBEC 12转化细胞系中均上调。此外，转化细胞显示EMT标记物的活化，包括SNAIL ZEB 1、Vim和MMP 2。所有转化的细胞系都有FOXA 1和FOXA 2的显著下调，表明在细胞转化和EMT中可能起作用。ChIP分析显示，在转化的HBEC 2细胞系中，FOXA 1和FOXA 2中组蛋白-H3和macroH 2A的结合增加，表明染色质致密。总之，长期致癌物暴露导致FOXA 1和FOXA 2下调伴随EMT的发生和HBEC细胞的体外转化。(C)2016年6月，作者。由Elsevier Ltd.发布。这是CC BY-NC-ND许可下的开放获取文章。
Lung cancer is largely an environmentally caused disease with poor prognosis. An in vitro transformation model of human bronchial epithelial cells (HBEC) was used to study long-term effects of tobacco smoke carcinogens on epithelial-mesenchymal transition (EMT) and the forkhead box transcription factors FOXA1 and FOXA2. CDK4 and hTERT immortalized HBEC2 and HBEC12 cell lines were exposed weekly to either cigarette smoke condensate (CSC), benzo[a]pyrene, or methylnitrosourea. Transformed cell lines were established from soft-agar colonies after 12 weeks of exposure. HBEC12 was transformed by all exposures while HBEC2 was only transformed by CSC. Untransformed HBEC2 showed little invasive capacity, whereas transformed cell lines completely closed the gap in a matrigel scratch wound assay. CDH1 was down-regulated in all of the transformed cell lines. In contrast, CDH2 was up-regulated in both HBEC2 and one of the HBEC12 transformed cell lines. Furthermore, transformed cells showed activation of EMT markers including SNAIL ZEB1, VIM, and MMP2. All transformed cell lines had significant down-regulation of FOXA1 and FOXA2, indicating a possible role in cell transformation and EMT. ChIP analysis showed increased binding of Histone-H3 and macroH2A in FOXA1 and FOXA2 in the transformed HBEC2 cell lines, indicating a compact chromatin. In conclusion, long-term carcinogen exposure lead to down regulation of FOXA1 and FOXA2 concomitantly with the occurrence of EMT and in vitro transformation in HBEC cells. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.