School of Medicine, University College Dublin, Dublin, Ireland; Department of Surgery, St. Vincent's University Hospital, Dublin, Ireland.
School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
Biochem Biophys Res Commun. 2021 May 21;554:179-185. doi: 10.1016/j.bbrc.2021.03.110. Epub 2021 Mar 30.
Inflammation is a pivotal pathological factor in colorectal cancer (CRC) initiation and progression, and modulating this inflammatory state has the potential to ameliorate disease progression. NR4A receptors have emerged as key regulators of inflammatory pathways that are important in CRC. Here, we have examined the effect of NR4A agonist, Cytosporone B (CsnB), on colorectal tissue integrity and its effect on the inflammatory profile in CRC tissue ex vivo. Here, we demonstrate concentrations up 100 μM CsnB did not adversely affect tissue integrity as measured using transepithelial electrical resistance, histology and crypt height. Subsequently, we reveal through the use of a cytokine/chemokine array, ELISA and qRT-PCR analysis that multiple pro-inflammatory mediators were significantly increased in CRC tissue compared to control tissue, which were then attenuated with the addition of CsnB (such as IL-1β, IL-8 and TNFα). Lastly, stratification of the data revealed that CsnB especially alters the inflammatory profile of tumours derived from males who had not undergone chemoradiotherapy. Thus, this study demonstrates that NR4A agonist CsnB does not adversely affect colon tissue structure or functionality and can attenuate the pro-inflammatory state of human CRC tissue ex vivo.
炎症是结直肠癌（CRC）发生和发展的关键病理因素，调节这种炎症状态有可能改善疾病进展。NR4A 受体已成为炎症途径的关键调节剂，这些途径在 CRC 中很重要。在这里，我们研究了 NR4A 激动剂 Cytosporone B（CsnB）对结直肠组织完整性的影响及其对 CRC 组织中炎症特征的影响。在这里，我们证明浓度高达 100μM 的 CsnB 不会如跨上皮电阻、组织学和隐窝高度所示的那样对组织完整性产生不利影响。随后，我们通过使用细胞因子/趋化因子阵列、ELISA 和 qRT-PCR 分析发现，与对照组织相比，CRC 组织中多种促炎介质显著增加，而 CsnB 的加入则减弱了这些介质（如 IL-1β、IL-8 和 TNFα）。最后，数据分层表明，CsnB 特别改变了未接受化疗和放疗的男性来源的肿瘤的炎症特征。因此，本研究表明，NR4A 激动剂 CsnB 不会对结肠组织结构或功能产生不利影响，并且可以减轻人类 CRC 组织的促炎状态。
