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bioRxiv · 10.1101/2023.03.13.532341

GPR4 knockout attenuates intestinal inflammation and forestalls the development of colitis-associated colorectal cancer in murine models

Marie, M. A.·Sanderlin, E. J.·Hoffman, A.·Cashwell, K. D.·Satturwar, S.·Hong, H.·Sun, Y.·Yang, L. V.
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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 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 GPR4 ablation alleviates intestinal inflammation and reduces tumor angiogenesis, development, and progression in the AOM/DSS mouse model. Author summaryInflammatory bowel disease (IBD), including ulcerative colitis and Crohns 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 using the DSS and AOM induced mouse models. GPR4 knockout alleviated intestinal inflammation, reduced tumor angiogenesis, and impeded CAC development. Our data suggest that inhibition of GPR4 may be explored as a potential therapeutic approach for IBD treatment and CAC prevention.

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Marie, M. A., Sanderlin, E. J., Hoffman, A., Cashwell, K. D., Satturwar, S., Hong, H., Sun, Y., Yang, L. V.. 2023-03-14. GPR4 knockout attenuates intestinal inflammation and forestalls the development of colitis-associated colorectal cancer in murine models. https://doi.org/10.1101/2023.03.13.532341

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