Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer
Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer
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NANOG 的减少介导阿司匹林对结直肠癌肿瘤生长和干性的抑制作用
DOI：
10.1159/000485405
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发表时间：
2017-01-01
影响因子：
--
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
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作者：
Wang, Hefei;Liu, Bing;Liu, Quentin
背景/目标：肿瘤干细胞（cancer stem cells，CSCs）被认为是肿瘤复发和转移的主要原因，是肿瘤治疗的潜在靶点。阿司匹林已被证明可以降低癌症风险和死亡率，特别是结肠直肠癌。然而，阿司匹林对CSC的抑制作用及其在结直肠癌中的相关机制仍不清楚。方法：CCK-8法检测细胞活力。通过球体形成试验、集落形成试验和ALDH 1试验来鉴定阿司匹林对CSC性质的影响。Western blotting检测干细胞因子的表达。采用异种移植瘤模型研究阿司匹林的体内抗肿瘤作用。采用非配对Student t检验、ANOVA检验和Kruskal-Wallis检验进行统计学比较。结果：阿司匹林可抑制结肠癌细胞的结肠球形成，减少ALDH 1阳性细胞数。阿司匹林抑制裸鼠移植瘤的生长，减少肿瘤细胞的干细胞。结论：阿司匹林降低了干细胞相关转录因子c-Myc、OCT 4和NANOG的蛋白表达。NANOG的抑制阻断了阿司匹林对球体形成的影响。相反，NANOG的异位表达挽救了阿司匹林抑制的球体形成，表明NANOG是关键的下游靶点。此外，我们发现阿司匹林通过降低NANOG的稳定性来抑制其在蛋白水平上的表达。总结：我们提供了新的证据表明阿司匹林通过下调NANOG减弱CSC特性，表明阿司匹林是一种有前途的结肠直肠癌治疗剂。
Background/Aims: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. Methods: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. Results: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. Conclusion: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.