The PI3K/AKT/c-MYC Axis Promotes the Acquisition of Cancer Stem-Like Features in Esophageal Squamous Cell Carcinoma

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• 作者：Hai-Feng Zhang ; Chengsheng Wu ; Abdulraheem Alshareef ; Nidhi Gupta ; Qing Zhao ; Xiu-E Xu ; Ji-Wei Jiao ; En-Min Li ; Li-Yan Xu and Raymond Lai
• 刊名：STEM CELLS
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：34
• 期：8
• 页码：2040-2051
• 全文大小：1315K
• ISSN：1549-4918

文摘

The importance of intratumoral heterogeneity has been highlighted by the identification and characterization of cancer stem cells (CSCs). Based on the differential responsiveness to a Sox2 reporter, SRR2, we had found a novel dichotomy in esophageal squamous cell carcinoma (ESCC) cells, with reporter-responsive (RR) cells showing more CSC-like features than reporter-unresponsive (RU) cells. Specifically, RR cells exhibited significantly higher tumorsphere formation capacity, proportions of CD44^High cells, chemoresistance to cisplatin, and tumorigenic potential in vivo. H₂O₂, a potent inducer of oxidative stress and reactive oxygen species, was found to induce a conversion from RU to RR cells; importantly, converted RR cells acquired CSC-like features. The PI3K/AKT/c-MYC signalling axis is important in this context, since pharmacologic blockade of PI3K-AKT or siRNA knockdown of c-MYC effectively inhibited the RR phenotype and its associated CSC-like features, as well as the H₂O₂-induced RU/RR conversion. In a cohort of 188 ESCC patient samples, we found a significant correlation between strong c-MYC expression and a short overall survival (p = .009). In conclusion, we have described a novel intratumoral heterogeneity in ESCC. The identification of the PI3K/AKT/c-MYC axis as a driver of CSC-like features carries therapeutic implications. Stem Cells 2016;34:2040–2051