Department of Pathology and Institute of Precision Medicine, Jining Medical University, 133 Hehua Road, Jining, 272067, China.
Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China.
Stem Cell Res Ther. 2020 Aug 27;11(1):370. doi: 10.1186/s13287-020-01884-4.
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.
阿司匹林的广泛认可的抗癌潜力引发了广泛的兴趣，以探索阿司匹林在癌症治疗中的临床益处。然而，目前对于阿司匹林抗癌潜力所涉及的分子机制的理解仍然有限。
进行了包含 ALDH、侧群、化疗耐药性、球体形成和肿瘤发生的癌症干性测定，以验证阿司匹林在体外和体内的功能。进行组蛋白修饰测定，以检查阿司匹林对组蛋白甲基化以及 HDAC 和 KDM6A/B 活性的影响。进行体内抑制剂测定，以评估各种抑制剂组合方式的治疗效果。
在体外研究方面，阿司匹林可降低三种癌症类型中癌细胞干性特性，包括减少 ALDH+亚群、侧群、化疗耐药性和球体形成。在体内研究方面，阿司匹林可降低肿瘤生长和转移，延长生存时间。此外，我们的结果表明，阿司匹林可抑制与炎症相关的干性基因表达（尤其是 ICAM3），该基因表达是通过高通量 siRNA 平台鉴定的。关于作用的潜在分子机制，阿司匹林可降低组蛋白去甲基酶（KDM6A/B）的表达，该酶介导组蛋白甲基化，并通过 COX 非依赖性方式抑制基因表达。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，可预防体内癌症进展。
上述发现提出了一个分子模型，解释了阿司匹林如何降低癌细胞干性特性。这些发现可能为涉及阿司匹林预防癌症进展的治疗策略提供新的靶点。
