Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.
Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.
Int J Mol Sci. 2024 Oct 30;25(21):11640. doi: 10.3390/ijms252111640.
Colorectal cancer represents one of the most serious complications of inflammatory bowel disease. The NLRP3 inflammasome plays a pivotal role in the onset and progression of inflammatory bowel disease and is also implicated in colorectal cancer. This study aimed to investigate whether NLRP3 deficiency or glyburide, a sulfonylurea used for diabetes management and known as an NLRP3 inhibitor, could suppress colitis and its related colorectal tumorigenesis. Mice were divided into three groups: a control group, a glyburide group, and an NLRP3-deficient group. We investigated acute colitis and inflammation-related tumor models using azoxymethane and dextran sodium sulfate. In the colitis model, the colonic inflammation grade was significantly increased in NLRP3-deficient mice but not in mice administered glyburide. In the colorectal carcinogenesis model, fewer colorectal tumors were observed in both NLRP3-deficient and glyburide-treated groups. Additionally, a reduction in the expression levels of inflammatory cytokine genes was detected in the colonic mucosa of the mice of these groups. These findings suggest that NLRP3 deficiency may exacerbate acute colitis, while pharmacological inhibition, as well as deficiency of NLRP3, suppresses colitis-related tumorigenesis, presumably due to the attenuation of chronic inflammation in the colorectum. Glyburide holds promise as a potential chemopreventive agent for colitis-related colorectal cancer.
结直肠癌是炎症性肠病最严重的并发症之一。NLRP3 炎性小体在炎症性肠病的发病和进展中起关键作用，也与结直肠癌有关。本研究旨在探讨 NLRP3 缺失或格列本脲（一种用于糖尿病管理的磺酰脲类药物，已知是 NLRP3 抑制剂）是否能抑制结肠炎及其相关的结直肠肿瘤发生。将小鼠分为三组：对照组、格列本脲组和 NLRP3 缺失组。我们使用氧化偶氮甲烷和葡聚糖硫酸钠建立了急性结肠炎和炎症相关肿瘤模型。在结肠炎模型中，NLRP3 缺失小鼠的结肠炎症程度显著增加，但格列本脲治疗的小鼠则没有。在结直肠癌变模型中，NLRP3 缺失和格列本脲治疗组的结直肠肿瘤数量均减少。此外，这些组小鼠的结肠黏膜中炎症细胞因子基因的表达水平降低。这些发现表明，NLRP3 缺失可能加重急性结肠炎，而药理学抑制以及 NLRP3 缺失抑制结肠炎相关肿瘤发生，可能是由于减少了结直肠的慢性炎症。格列本脲有望成为一种治疗结肠炎相关结直肠癌的化学预防剂。
