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)