GPR4 Knockout Attenuates Intestinal Inflammation and Forestalls the Development of Colitis-Associated Colorectal Cancer in Murine Models.
GPR4 Knockout Attenuates Intestinal Inflammation and Forestalls the Development of Colitis-Associated Colorectal Cancer in Murine Models.
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DOI：
10.3390/cancers15204974
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发表时间：
2023-10-13
期刊：
影响因子：
5.2
通讯作者：
Yang, Li V.
中科院分区：
文献类型：
--
作者：
Marie, Mona A.;Sanderlin, Edward J.;Hoffman, Alexander P.;Cashwell, Kylie D.;Satturwar, Swati;Hong, Heng;Sun, Ying;Yang, Li V.
关键词：
炎症性肠病(IBD)，包括溃疡性结肠炎和克罗恩病，是一种慢性消化道炎症，使人虚弱。与普通人群相比，IBD患者患结肠炎相关性结直肠癌(CAC)的风险更高。IBD的病因还不是很清楚，但遗传和环境因素都有牵连。在这项研究中，我们研究了pH敏感的GPR4受体在结肠炎和CAC小鼠模型中的作用。GPR4基因敲除可减轻肠道炎症，减少肿瘤血管生成，并阻碍CAC的发展。我们的数据表明，抑制GPR4可能成为治疗IBD和预防CAC的潜在治疗方法。GPR4是一种质子敏感的G蛋白偶联受体，在血管内皮细胞中高表达，已被证明可以加强小鼠结肠炎模型的肠道炎症。在此，我们使用葡聚糖硫酸钠(DSS)和偶氮甲烷(AOM)小鼠模型在野生型和GPR4基因敲除小鼠中评估了GPR4在结肠炎相关结直肠癌(CAC)发生中的促炎作用。我们发现GPR4参与了慢性肠道炎症，并增加了DSS/AOM诱导的肠道肿瘤负担。GPR4缺陷小鼠肿瘤血管密度明显减少，与肿瘤坏死增加、肿瘤细胞增殖减少有关。这些数据表明，在AOM/DSS小鼠模型中，GPR4消融可以减轻肠道炎症，减少肿瘤血管的生成、发展和进展。
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. 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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影响因子：
24.1
作者：
Bertheloot D;Latz E;Franklin BS
通讯作者：
Franklin BS
影响因子：
--
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通讯作者：
Khanum, Shaukath Ara
影响因子：
5.8
作者：
Krewson, Elizabeth A.;Sanderlin, Edward J.;Yang, Li V.
通讯作者：
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影响因子：
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作者：
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影响因子：
9
作者：
Li R;Guan Z;Bi S;Wang F;He L;Niu X;You Y;Liu Y;Ding Y;Siwko S;Wang N;Zhang Z;Jin Y;Luo J
通讯作者：
Luo J