上皮细胞 RAD50 的缺乏会通过 IL-6 介导的 JAK1/2-STAT3 信号转导加重 UC,并促进小鼠结肠炎相关癌症的发展。

Jie Zhang, Mengli Yu, Tiantian Zhang, Xin Song, Songmin Ying, Zhe Shen, Chaohui Yu
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引用次数: 0

摘要

背景:溃疡性结肠炎(UC溃疡性结肠炎(UC)是罹患结肠炎相关癌症(CAC)的最重要风险因素之一。持续的 DNA 损伤会增加 CAC 风险,在 UC 患者中也观察到了这种损伤。我们旨在确定DNA双链断裂(DSB)传感器RAD50在UC进展为CAC过程中的调控作用:方法:对 IBD 和 CAC 细胞及小鼠模型中的 DSB 和 RAD50 表达进行评估。方法:对 IBD 和 CAC 细胞及小鼠模型中的 DSB 和 RAD50 表达进行评估,并利用肠上皮 RAD50 缺失小鼠(RAD50IEC-KO)研究 RAD50 在结肠炎和 CAC 中的作用:结果:随着结肠炎和 CAC 模型中 γ-H2AX 表达的增加,RAD50 在人类 IBD 和 CAC 以及小鼠模型中的表达也减少了。此外,RAD50IEC-KO 使小鼠对葡聚糖硫酸钠(DSS)诱导的急性和慢性实验性结肠炎敏感。RNA-seq分析显示,RAD50激活了细胞因子-细胞因子受体反应,这种反应通过JAK-STAT途径被放大。RAD50直接与STAT3相互作用,随后抑制其磷酸化,这可能会破坏IL-6-JAK1/2-STAT3-IL-6前馈环。药理 STAT3 抑制可缓解 RAD50IEC-KO 小鼠的结肠炎。在 RAD50 缺失的细胞中发现了严重的 DSBs、细胞增殖增加和炎症反应延长,这促进了 RAD50IEC-KO 小鼠的偶氮甲烷(AOM)-DSS 诱导的结肠肿瘤发生:结论:RAD50 在结肠炎中具有抗 IL-6 相关炎症作用,并能抑制 CAC。结论:RAD50能在结肠炎中发挥抗IL-6相关炎症作用并抑制CAC,提高结肠组织中的RAD50水平可能有望治疗UC和CAC患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Deficiency in epithelium RAD50 aggravates UC via IL-6-mediated JAK1/2-STAT3 signaling and promotes development of colitis-associated cancer in mice.

Background: Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC.

Methods: DSBs and RAD50 expression in IBD and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC.

Results: Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50 activated the cytokine-cytokine receptor response, which was amplified through the JAK-STAT pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice.

Conclusion: RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.

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