| RRC ID |
85088
|
| Author |
Iguchi E, Takai A, Oe N, Fujii Y, Omatsu M, Takeda H, Shimizu T, Maruno T, Nakanishi Y, Yoshinaga M, Maruyama T, Marusawa H, Obama K, Takeuchi O, Seno H.
|
| Title |
Epithelial Regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of NFKBIZ mRNA.
|
| Journal |
Proc Natl Acad Sci U S A
|
| Abstract |
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 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.
|
| Volume |
122(23)
|
| Pages |
e2500820122
|
| Published |
2025-6-10
|
| DOI |
10.1073/pnas.2500820122
|
| PMID |
40460118
|
| MeSH |
Adaptor Proteins, Signal Transducing
Animals
Cell Proliferation
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Gene Expression Regulation, Neoplastic
Humans
Interleukin-17* / genetics
Interleukin-17* / metabolism
Intestinal Mucosa / metabolism
Intestinal Mucosa / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
RNA Stability
RNA, Messenger / genetics
RNA, Messenger / metabolism
Ribonucleases* / genetics
Ribonucleases* / metabolism
Signal Transduction
Transcription Factors* / genetics
Transcription Factors* / metabolism
|
| Resource |
| Mice |
RBRC06410 |
