FOXC2 promotes epithelial-mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells
FOXC2 promotes epithelial-mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells
复制标题
FOXC2促进非小细胞肺癌细胞上皮-间质转化和顺铂耐药
DOI：
10.1007/s00280-018-3697-2
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发表时间：
2018-12-01
影响因子：
3
通讯作者：
Wei, Li
中科院分区：
文献类型：
--
作者：
He, Yuwen;Xie, Hui;Wei, Li
目的铂类药物，特别是顺铂（DDP），用于治疗非小细胞肺癌（NSCLC）。然而，耐药的发展仍然是NSCLC治疗的主要障碍。方法采用基因芯片技术，从A549/DDP顺铂耐药细胞的转录组中筛选出潜在的顺铂耐药相关基因。增益和功能丧失的测定进行分析叉头盒蛋白C2（FOXC 2）在体外和体内的敏感性NSCLC细胞顺铂及其可能的分子mechanism.ResultsUsing全球转录组分析，我们发现，FOXC 2是一个最上调的分子在A549/DDP细胞相比，A549细胞。我们进一步证实了FOXC 2在顺铂耐药的NSCLC组织中的表达显著增加。FOXC 2基因敲低可显著增加A549/DDP细胞对顺铂的体外和体内敏感性，而FOXC 2基因过表达可增加顺铂敏感性NSCLC细胞对顺铂的耐药性。此外，我们发现FOXC 2通过诱导NSCLC细胞的上皮-间质转化（EMT）来促进顺铂耐药。此外，FOXC 2还激活了AKT/GSK 3信号通路，进而增加了EMT相关转录因子Snail的蛋白表达。结论FOXC 2通过激活AKT/GSK 3/Snail/EMT信号通路增强NSCLC细胞对顺铂的耐药性，有望成为治疗NSCLC耐药的新靶点。
PurposePlatinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC.MethodsThe potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms.ResultsUsing global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial-mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3 signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells.ConclusionFOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.