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GPR4 Knockout Attenuates Intestinal Inflammation and Forestalls the Development of Colitis-Associated Colorectal Cancer in Murine Models
SIMPLE SUMMARY: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a debilitating condition with chronic inflammation in the digestive tract. Patients with IBD are at higher risk of developing colitis-associated colorectal cancer (CAC) compared with the general po...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605520/ https://www.ncbi.nlm.nih.gov/pubmed/37894341 http://dx.doi.org/10.3390/cancers15204974 |
Sumario: | SIMPLE SUMMARY: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a debilitating condition with chronic inflammation in the digestive tract. Patients with IBD are at higher risk of developing colitis-associated colorectal cancer (CAC) compared with the general population. The etiology of IBD is not well understood, but both genetic and environmental factors have been implicated. In this study, we investigated the role of the pH-sensing GPR4 receptor in colitis and CAC mouse models. GPR4 knockout alleviated intestinal inflammation, reduced tumor angiogenesis, and impeded CAC development. Our data suggest that the inhibition of GPR4 may be explored as a potential therapeutic approach for IBD treatment and CAC prevention. ABSTRACT: GPR4 is a proton-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and has been shown to potentiate intestinal inflammation in murine colitis models. Herein, we evaluated the proinflammatory role of GPR4 in the development of colitis-associated colorectal cancer (CAC) using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse models in wild-type and GPR4 knockout mice. We found that GPR4 contributed to chronic intestinal inflammation and heightened DSS/AOM-induced intestinal tumor burden. Tumor blood vessel density was markedly reduced in mice deficient in GPR4, which correlated with increased tumor necrosis and reduced tumor cell proliferation. These data demonstrate that GPR4 ablation alleviates intestinal inflammation and reduces tumor angiogenesis, development, and progression in the AOM/DSS mouse model. |
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