Background

Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood.

Methods

We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells.

Results

ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model.

Conclusions

ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

中文翻译：

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阿司匹林通过抑制假定的癌症干细胞增强顺铂对食管鳞状细胞癌的治疗效果

背景

癌症干细胞（CSC）与食管鳞状细胞癌（ESCC）患者的预后、复发和治疗耐药有关。尽管越来越多的证据表明阿司匹林（乙酰水杨酸，ASA）可以降低食管鳞癌的发病率并改善预后，但其机制仍有待充分了解。

方法

我们研究了 ASA 在人 ESCC 细胞系和 N-亚硝基甲基苄胺诱导的大鼠 ESCC 致癌模型中化疗/化学预防中的作用。体外和体内检查了 ASA/顺铂联合治疗对 ESCC 细胞系的影响。使用富含推定 CSC (pCSC) 的球形形成细胞来研究 ASA 对 CSC 的影响。采用高通量测序 (ATAC-seq) 进行转座酶可及染色质检测，以确定 ASA 在 ESCC 细胞中引起的染色质可及性的改变。

结果

ASA 抑制 CSC 特性并增强顺铂对人 ESCC 细胞的治疗作用。ATAC-seq 表明 ASA 治疗通过组蛋白乙酰化水平的改变，导致 ESCC 细胞（尤其是 pCSC）染色质发生显着的表观遗传改变。表观遗传变化激活 Bim 表达并促进 ESCC 的 CSC 细胞死亡。此外，ASA 还可预防大鼠模型中 NMBzA 诱导的 ESCC 的致癌作用。

结论

ASA可能成为食管鳞癌治疗的潜在化疗辅助剂和化学预防药物。