Iguchi Eriko, Takai Atsushi, Oe Natsumi, Fujii Yosuke, Omatsu Mayuki, Takeda Haruhiko, Shimizu Takahiro, Maruno Takahisa, Nakanishi Yuki, Yoshinaga Masanori, Maruyama Takashi, Marusawa Hiroyuki, Obama Kazutaka, Takeuchi Osamu, Seno Hiroshi
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2500820122. doi: 10.1073/pnas.2500820122. Epub 2025 Jun 3.
Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. 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 mouse model lacking in intestinal epithelia. 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 , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to 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 knockout mouse model demonstrated that the tumor-suppressive effect of depended on expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low expression in colorectal cancer tissue was related to poor prognosis. Therefore, represses colon tumor growth by regulating IL-17 signaling via mRNA degradation. could be a potential therapeutic target in colon tumors.
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。它被鉴定为溃疡性结肠炎患者炎症性结肠上皮中频繁突变的基因之一；然而，其在肿瘤发生过程中在肠上皮细胞中的意义仍不清楚。因此，我们构建了一种肠道上皮细胞中缺乏Regnase-1的小鼠模型。Regnase-1缺失显著促进结肠肿瘤生长，同时肿瘤组织中细胞外信号调节激酶（ERK）磷酸化水平升高。对肿瘤组织的转录组分析表明，白细胞介素（IL）-17信号通路的介质RORγt是肠细胞中Regnase-1的主要降解靶点，且Regnase-1缺乏增强了IL-17信号。用抗生素或IL-17中和抗体治疗可消除因Regnase-1缺失导致的结肠肿瘤增殖效应，这表明Regnase-1对结肠肿瘤生长的保护作用依赖于肠道微生物触发的IL-17信号。对Regnase-1基因敲除小鼠模型的分析表明，Regnase-1的肿瘤抑制作用依赖于RORγt表达。值得注意的是，口服富马酸二甲酯（一种Regnase-1蛋白失活的潜在抑制剂）可抑制肿瘤生长、下调RORγt并抑制ERK激活。此外，TCGA数据分析显示，结直肠癌组织中Regnase-1低表达与预后不良相关。因此，Regnase-1通过降解RORγt mRNA调节IL-17信号来抑制结肠肿瘤生长。Regnase-1可能是结肠肿瘤的一个潜在治疗靶点。
