Aldehyde dehydrogenase 3A1 is robustly upregulated in gastric cancer stem-like cells and associated with tumorigenesis
Aldehyde dehydrogenase 3A1 is robustly upregulated in gastric cancer stem-like cells and associated with tumorigenesis
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DOI：
10.3892/ijo.2016.3551
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发表时间：
2016-08-01
影响因子：
5.2
通讯作者：
Zhang, Ren-Chao
中科院分区：
文献类型：
--
作者：
Wu, Di;Mou, Yi-Ping;Zhang, Ren-Chao
增强的乙醛脱氢酶 (ALDH) 活性已被证明是癌症干细胞 (CSC) 的标志。最近的证据表明，它作为干细胞相关标记物的作用取决于特定的亚型。然而，人们对胃癌中醛氟活性的特定 ALDH 异构体知之甚少。在本研究中，我们通过 Aldeflor 测定从 2 种人胃癌细胞系 MKN-45 和 SGC-7901 中分离出 ALDH(bright) 细胞，并发现其自我更新、分化和致瘤性增强，作为干性特征的证明。我们还发现 ALDH（bright）细胞表达的 E-钙粘蛋白水平降低，但 Snail 和 Vimentin 水平升高，表明上皮-间质转化（EMT）表型可能导致转移潜力增强。由于基于 ALDH 患病率的进一步研究和预后应用需要对特定 ALDH 亚型进行定量，因此我们通过定量实时聚合酶链反应 (qRT-PCR) 表征了分选的胃癌细胞系中所有 19 种 ALDH 亚型的表达。与非干细胞相比，在这些胃癌干细胞样细胞中观察到 ALDH-3A1 的强烈上调。此外，我们对93例固定的患者胃肿瘤样本进行了免疫组织学分析，发现ALDH-3A1表达与胃癌不典型增生以及分级、分化、淋巴结转移和癌症分期密切相关。因此，我们的数据提供了强有力的证据，表明 ALDH-3A1 是一种新型胃癌干细胞相关标记物，具有潜在的预后价值，并证明 ALDH-3A1 患病率与胃癌进展之间存在明确的关联。
Enhanced aldehyde dehydrogenase (ALDH) activity has been shown to serve as a hallmark for cancer stem cells (CSCs). Recent evidence suggests that its role as a stem cell-related marker has come down to the specific isoform. However, little is known about the specific ALDH isoform contributing to aldefluor activity in gastric cancer. In this study, we isolated ALDH(bright) cells from 2 human gastric cancer cell lines MKN-45 and SGC-7901 by using an Aldefluor assay and found elevated self-renewal, differentiation and tumorigenicity, as demonstration of stemness characteristics. We also found that ALDH(bright) cells expressed decreased levels of E-cadherin but increased levels of Snail and Vimentin, indication of an epithelial-mesenchymal transition (EMT) phenotype which may be responsible for the enhanced metastatic potential. Since further research and prognostic application based on ALDH prevalence require the quantification of the specific ALDH isoform, we characterized the expression of all 19 ALDH isoforms in the sorted gastric cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Compared with the non-stem counterparts, robust upregulation of ALDH-3A1 was observed in these gastric cancer stem like cells. Furthermore, we performed immunohistological analysis on 93 fixed patient gastric tumor samples and found that ALDH-3A1 expression correlated well with gastric cancer dysplasia and grades, differentiation, lymph node metastasis and cancer stage. Our data, therefore, provide strong evidence that ALDH-3A1 is a novel gastric cancer stem cell related marker with potential prognostic values and demonstrate a clear association between ALDH-3A1 prevalence and gastric cancer progression.