Epithelial Regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of <i>NFKBIZ</i> mRNA.

Abstract

Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. <i>Regnase-1</i> 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 <i>Apc^Min/+</i> mouse model lacking <i>Regnase-1</i> in intestinal epithelia. <i>Regnase-1</i> 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 <i>Nfkbiz</i>, a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that <i>Regnase-1</i> deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to <i>Regnase-1</i> 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 <i>Nfkbiz</i> knockout mouse model demonstrated that the tumor-suppressive effect of <i>Regnase-1</i> depended on <i>Nfkbiz</i> expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated <i>Nfkbiz</i>, and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low <i>Regnase-1</i> expression in colorectal cancer tissue was related to poor prognosis. Therefore, <i>Regnase-1</i> represses colon tumor growth by regulating IL-17 signaling via <i>Nfkbiz</i> mRNA degradation. <i>Regnase-1</i> could be a potential therapeutic target in colon tumors.