Reference - Detail
RRC ID | 82104 |
---|---|
Author | Li X, Kurahara LH, Zhao Z, Zhao F, Ishikawa R, Ohmichi K, Li G, Yamashita T, Hashimoto T, Hirano M, Sun Z, Hirano K. |
Title | Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis. |
Journal | Cell Mol Gastroenterol Hepatol |
Abstract |
BACKGROUND & AIMS:Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis. METHODS:A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases. RESULTS:AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site. CONCLUSIONS:PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis. |
Volume | 18(1) |
Pages | 105-131 |
Published | 2024-1-1 |
DOI | 10.1016/j.jcmgh.2024.04.001 |
PII | S2352-345X(24)00071-7 |
PMID | 38614455 |
PMC | PMC11127032 |
MeSH | Animals Azoxymethane* / toxicity Caco-2 Cells Carcinogenesis / drug effects Carcinogenesis / pathology Colitis / chemically induced Colitis / complications Colitis / drug therapy Colitis / pathology Colitis-Associated Neoplasms / drug therapy Colitis-Associated Neoplasms / immunology Colitis-Associated Neoplasms / microbiology Colitis-Associated Neoplasms / pathology Crohn Disease / chemically induced Crohn Disease / drug therapy Crohn Disease / microbiology Crohn Disease / pathology Dextran Sulfate* / toxicity Disease Models, Animal* Gastrointestinal Microbiome* / drug effects Humans Male Mice Mice, Inbred C57BL Myofibroblasts / drug effects Myofibroblasts / metabolism Myofibroblasts / pathology Receptor, PAR-1* / antagonists & inhibitors Receptor, PAR-1* / metabolism STAT3 Transcription Factor / metabolism Thrombin / metabolism |
Resource | |
Human and Animal Cells | CACO-2(RCB0988) |