Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. Regnase-1 was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an Apc Min/+ mouse model lacking Regnase-1 in intestinal epithelia. Regnase-1 deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that Nfkbiz , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that Regnase-1 deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to Regnase-1 deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the Nfkbiz knockout mouse model demonstrated that the tumor-suppressive effect of Regnase-1 depended on Nfkbiz expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated Nfkbiz , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low Regnase-1 expression in colorectal cancer tissue was related to poor prognosis. Therefore, Regnase-1 represses colon tumor growth by regulating IL-17 signaling via Nfkbiz mRNA degradation. Regnase-1 could be a potential therapeutic target in colon tumors.

中文翻译：

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Epithelial Regnase-1 通过降解 NFKBIZ mRNA 调节 IL-17 信号传导，从而抑制结直肠肿瘤生长

Regnase-1 是一种核糖核酸酶，通过降解细胞因子 mRNA 来调节免疫细胞中的炎症。Regnase-1 被确定为溃疡性结肠炎患者发炎的结直肠上皮中经常突变的基因之一;然而，它在致瘤过程中对肠上皮细胞的意义仍然未知。因此，我们开发了一种在肠上皮细胞中缺乏 Regnase-1 的 Apc Min/+ 小鼠模型。Regnase-1 缺失显著促进了结肠肿瘤的生长，同时肿瘤组织中细胞外信号调节激酶 （ERK） 磷酸化水平升高。肿瘤组织的转录组分析显示，Nfkbiz 是白细胞介素 （IL）-17 信号通路的介质，是肠皮细胞中 Regnase-1 的主要降解靶标，Regnase-1 缺陷增强了 IL-17 信号传导。抗生素或 IL-17 中和抗体治疗消除了由于 Regnase-1 缺失而导致的结肠肿瘤增殖作用，表明 Regnase-1 对结肠肿瘤生长的保护作用取决于肠道微生物触发的 IL-17 信号传导。Nfkbiz 敲除小鼠模型的分析表明，Regnase-1 的肿瘤抑制作用取决于 Nfkbiz 表达。值得注意的是，富马酸二甲酯（Regnase-1 蛋白灭活的潜在抑制剂）的口服治疗抑制了肿瘤生长，下调了 Nfkbiz ，并抑制了 ERK 活化。此外，TCGA 数据分析显示，结直肠癌组织中低 Regnase-1 表达与不良预后相关。因此，Regnase-1 通过 Nfkbiz mRNA 降解调节 IL-17 信号传导，从而抑制结肠肿瘤生长。Regnase-1 可能是结肠肿瘤的潜在治疗靶点。