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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 122; no. 23; p. e2500820122
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.06.2025
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antibiotics; Cell Proliferation; Colon; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Data analysis; Degradation; Deletion; Enterocytes; Epithelial cells; Epithelium; Extracellular signal-regulated kinase; Gene Expression Regulation, Neoplastic; Humans; Immune system; Inflammation; Interleukin 17; Interleukin-17 - genetics; Interleukin-17 - metabolism; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Ribonucleases - genetics; Ribonucleases - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Therapeutic targets; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomes; Tumors; Ulcerative colitis; Regnase-1; colorectal cancer; IL-17
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2500820122

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.