SNAIL Induces Epithelial-to-Mesenchymal Transition and Cancer Stem Cell-Like Properties in Aldehyde Dehydroghenase-Negative Thyroid Cancer Cells
SNAIL Induces Epithelial-to-Mesenchymal Transition and Cancer Stem Cell-Like Properties in Aldehyde Dehydroghenase-Negative Thyroid Cancer Cells
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DOI：
10.1089/thy.2012.0319
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发表时间：
2013-08-01
期刊：
影响因子：
6.6
通讯作者：
Nagayama, Yuji
中科院分区：
文献类型：
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作者：
Yasui, Kazuaki;Shimamura, Mika;Nagayama, Yuji
背景资料：上皮间质转化（EMT）被认为在肿瘤的侵袭和转移中起关键作用，并与肿瘤干细胞（CSC）的特性相关。目前尚不清楚甲状腺癌中EMT和CSC之间是否存在联系。因此，我们研究了接受EMT的甲状腺癌的CSC特性。方法：诱导急救在上皮型甲状腺癌细胞系ACT-1中（梭形细胞形态，上皮标记物E-cadherin和间充质标记物vimentin分别表达的丧失和获得），我们使用转化生长因子-β在一个实施方案中，所述抗体包含TGF-beta（TGF-β）、BRAF（V600 E）和/或Snail同源物1（SNAI 1，也称为SNAIL）。CSC的特性进行了分析与细胞增殖，化疗敏感性，在体外和体内肿瘤形成能力，细胞表面抗原，和细胞内醛脱氢酶（ALDH;一个已知的CSC标记）activities.Results：EMT诱导最有效的SNAIL（ACT-SNAIL细胞），而TGF-β和BRAF（V600 E）效率较低。ACT-SNAIL细胞在体外球体试验中显示出轻微但显著增强的肿瘤形成能力（约3倍），但在体内皮下肿瘤生长试验中没有，并且与亲本ACT-1细胞相比显示出相当的化学敏感性。然而，有趣的是，尽管ALDH（+）细胞的体外球体形成能力在SNAIL诱导后几乎没有变化，但SNAIL过表达在ALDH（-）细胞中诱导了高得多的球体（约14倍）。因此，ALDH不再是ACT-SNAIL细胞中的CSC标记物。结论：所有这些数据表明，EMT赋予ALDH（-）细胞中的CSC特性，并且似乎影响ALDH富集CSC的能力。
Background: Epithelial-to-mesenchymal transition (EMT) is thought to play a critical role in the invasion and metastasis of cancer and to be associated with cancer stem cell (CSC) properties. It is not clear if there is a link between EMT and CSCs in thyroid cancers. We therefore investigated the CSC properties of thyroid cancers that underwent EMT.Method: To induce EMT (spindle-like cell morphology, loss and acquisition of expression of an epithelial marker E-cadherin and a mesenchymal marker vimentin respectively) in an epithelial-type thyroid cancer cell line ACT-1, we used transforming growth factor-beta (TGF-beta), BRAF(V600E), and/or Snail homolog 1 (SNAI1, also known as SNAIL). CSC properties were analyzed with assays for cell proliferation, chemosensitivity, in vitro and in vivo tumor formation ability, cell surface antigens, and intracellular aldehyde dehydrogenase (ALDH; a known CSC marker) activities.Results: EMT was induced most efficiently by SNAIL (ACT-SNAIL cells), whereas TGF-beta and BRAF(V600E) were less efficient. ACT-SNAIL cells showed slightly but significantly enhanced tumor formation ability in an in vitro sphere assay (approximately 3-fold) but not an in vivo subcutaneous tumor growth assay, and showed comparable chemosensitivity compared with the parental ACT-1 cells. However, of interest, although the in vitro sphere-formation ability of ALDH(+) cells was almost unchanged after SNAIL induction, SNAIL overexpression induced much higher (approximately 14-fold) spheres in ALDH(-) cells. Thus, ALDH was no longer a CSC marker in ACT-SNAIL cells.Conclusions: All these data indicate that EMT confers CSC properties in ALDH(-) cells and appears to influence the ability of ALDH to enrich CSCs.