School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China; Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China; Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
Eur J Pharmacol. 2021 Sep 5;906:174173. doi: 10.1016/j.ejphar.2021.174173. Epub 2021 May 23.
According to numerous epidemiological studies, aspirin is a non-steroidal anti-inflammatory drug (NSAID) that reduces the occurrence and mortality of colorectal cancer (CRC). However, the underlying mechanisms are not well identified. In an effort to fill these gaps, we administered aspirin on mice one day before induction in an azoxymethane (AOM)/dextran sulfate sodium (DSS) induced CRC model. In this study, we assessed the effects of aspirin on tumorigenesis and tumor cell proliferation. Multi-layer analyses were carried out to identify changes in cytokines, metabolites, level of gene expressions, and proteins associated with tumorigenesis and aspirin treatment. The results showed that aspirin-treated mice developed fewer colon tumors in response to AOM/DSS, and aspirin can actively block cyclooxygenase (COX) metabolism and reduce levels of pro-inflammatory cytokines. In addition, the transcriptomic and proteomic analyses both indicated that aspirin has an inhibitory effect on the Wnt pathway. The in vitro results further indicated that aspirin inhibits WNT6 production, possibly by suppressing its transcription factor NR4A2, which in turn is regulated by prostaglandin E2, thereby ultimately inhibiting the Wnt pathway. These findings improve our understanding of the mechanisms behind aspirin's chemoprevention effect on CRC.
根据大量的流行病学研究，阿司匹林是一种非甾体抗炎药（NSAID），可降低结直肠癌（CRC）的发生和死亡率。然而，其潜在机制尚未得到很好的阐明。为了填补这些空白，我们在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的 CRC 模型中，在诱导前一天给小鼠施用阿司匹林。在这项研究中，我们评估了阿司匹林对肿瘤发生和肿瘤细胞增殖的影响。进行了多层分析，以确定与肿瘤发生和阿司匹林治疗相关的细胞因子、代谢物、基因表达水平和蛋白质的变化。结果表明，阿司匹林治疗的小鼠对 AOM/DSS 的反应中结肠肿瘤的形成较少，并且阿司匹林可以积极阻断环氧化酶（COX）代谢并降低促炎细胞因子的水平。此外，转录组和蛋白质组分析均表明阿司匹林对 Wnt 通路具有抑制作用。体外结果进一步表明，阿司匹林抑制 WNT6 的产生，可能是通过抑制其转录因子 NR4A2，而后者又受前列腺素 E2 调节，从而最终抑制 Wnt 通路。这些发现提高了我们对阿司匹林预防 CRC 化学作用背后机制的理解。
