NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells.
NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells.
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DOI：
10.1371/journal.pone.0068597
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mayo MW
中科院分区：
文献类型：
--
作者：
Kumar M;Allison DF;Baranova NN;Wamsley JJ;Katz AJ;Bekiranov S;Jones DR;Mayo MW
上皮向间充质转化(EMT)是一种去分化过程，与实体瘤的转移和肿瘤起始细胞(CICs)的产生有关。为了研究非小细胞肺癌的内皮细胞转移，我们利用了三维细胞培养系统，在该系统中细胞与肿瘤坏死因子α和转化生长因子ββ共刺激。NSCLC球体培养细胞表达EMT主开关转录因子Twist1、SNAI1/Snail1、SNAI2/slug和ZEB2/SIP1，具有高度侵袭性。间充质NSCLC培养呈现CIC特征，表现出转录因子KLF4、SOX2、Pou5f1/Oct4、MYCN和KIT的高表达。因此，这些假定的CIC通过在有限的细胞稀释下形成肺转移而显示出癌症的“干细胞样”表型。多效性转录因子NF-κB参与了子宫内膜癌的发生和转移。因此，我们着手建立一个非小细胞肺癌模型，以进一步研究NF-κB激活在CICs发生发展中的作用。在这里，我们证明了3D培养中EMT的诱导导致了结构性的NF-κB活性。此外，抑制NF-κB导致Twist1、SNAI2和ZEB2诱导的丢失，细胞不能侵袭和转移。我们的工作表明，NF-κB在非小细胞肺癌转移中是必需的，部分是通过转录上调EMT所需的主开关转录因子来实现的。
The epithelial-to-mesenchymal transition (EMT) is a de-differentiation process that has been implicated in metastasis and the generation of cancer initiating cells (CICs) in solid tumors. To examine EMT in non-small cell lung cancer (NSCLC), we utilized a three dimensional (3D) cell culture system in which cells were co-stimulated with tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGFβ). NSCLC spheroid cultures display elevated expression of EMT master-switch transcription factors, TWIST1, SNAI1/Snail1, SNAI2/Slug and ZEB2/Sip1, and are highly invasive. Mesenchymal NSCLC cultures show CIC characteristics, displaying elevated expression of transcription factors KLF4, SOX2, POU5F1/Oct4, MYCN, and KIT. As a result, these putative CIC display a cancer “stem-like” phenotype by forming lung metastases under limiting cell dilution. The pleiotropic transcription factor, NF-κB, has been implicated in EMT and metastasis. Thus, we set out to develop a NSCLC model to further characterize the role of NF-κB activation in the development of CICs. Here, we demonstrate that induction of EMT in 3D cultures results in constitutive NF-κB activity. Furthermore, inhibition of NF-κB resulted in the loss of TWIST1, SNAI2, and ZEB2 induction, and a failure of cells to invade and metastasize. Our work indicates that NF-κB is required for NSCLC metastasis, in part, by transcriptionally upregulating master-switch transcription factors required for EMT.
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