The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anti-cancer potential of aspirin remains limited. Cancer stemness assays which contained ALDH, side population, chemo-resistance, sphere formation, and tumorigenesis were performed to validate aspirin function in vitro and in vivo. Histone modification assay was performed to check the effect of aspirin on histone methylation as well as the activity of HDAC and KDM6A/B. Inhibitor in vivo assay was performed to evaluate therapeutic effects of various inhibitor combination manners. In regards to in vitro studies, aspirin diminishes cancer cell stemness properties which include reducing the ALDH+ subpopulation, side population, chemo-resistance, and sphere formation in three cancer types. In regards to in vivo studies, aspirin decreases tumor growth and metastasis and prolongs survival. In addition, our results showed that aspirin inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regards to the underlying molecular mechanism of action, aspirin reduces histone demethylase (KDM6A/B) expression that mediates histone methylation and suppresses gene expression via a COX-independent manner. In regards to therapeutic strategies, aspirin combined HDM inhibitors, ICAM3 downstream signaling Src/PI3K inhibitors, or ICAM3 inhibitor Lifitigrast prevents cancer progression in vivo. The aforementioned findings suggest a molecular model that explains how aspirin diminishes cancer cell stemness properties. These findings may provide novel targets for therapeutic strategies involving aspirin in the prevention of cancer progression.

中文翻译：

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阿司匹林介导组蛋白甲基化，其通过与COX无关的方式抑制炎症相关干基因表达，从而减少癌症干。

阿司匹林具有广泛的抗癌潜力，引起人们广泛兴趣，探讨阿司匹林在癌症治疗中的临床益处。但是，目前对阿司匹林抗癌潜力涉及的分子机制的了解仍然有限。进行了包含ALDH，侧群，化学耐药性，球形成和肿瘤发生的癌干分析，以验证阿司匹林在体内和体外的功能。进行组蛋白修饰测定以检查阿司匹林对组蛋白甲基化的作用以及HDAC和KDM6A / B的活性。进行抑制剂体内试验以评价各种抑制剂组合方式的治疗效果。在体外研究方面，阿司匹林可降低癌细胞的干性，包括减少ALDH +亚群，侧群，三种癌症类型的化学抗性和球形成。关于体内研究，阿司匹林可减少肿瘤的生长和转移并延长生存期。此外，我们的结果表明，阿司匹林可抑制由高通量siRNA平台鉴定的炎症相关干基因表达（特别是ICAM3）。关于潜在的分子作用机制，阿司匹林降低介导组蛋白甲基化的组蛋白脱甲基酶（KDM6A / B）表达，并通过独立于COX的方式抑制基因表达。关于治疗策略，阿司匹林联合HDM抑制剂，ICAM3下游信号Src / PI3K抑制剂或ICAM3抑制剂Lifitigrast可预防体内癌症的发展。前述发现提示了一种分子模型，该模型解释了阿司匹林如何减少癌细胞干性。