Epithelial Regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of NFKBIZ mRNA

• 成果类型: Article
• 署名作者: 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
• 署名单位: Kyoto University; Kyoto University; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR); Osaka Red Cross Hospital; Kyoto University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13124
• DOI: 10.1073/pnas.2500820122
• 发表日期: 2025-06-10
• 关键词: kappa-b-zeta; breast-cancer cells; interleukin-17 receptor; gene-expression; activation; chemokine; tumorigenesis; progression; mutations; promote

摘要

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 ApcMin/+ 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 treatment of dimethyl fumarate, a potential inhibitor of Regnase- 1 protein inactivaFurthermore, 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.