Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Gastroenterology. 2021 Mar;160(4):1256-1268.e9. doi: 10.1053/j.gastro.2020.11.006. Epub 2020 Nov 13.
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis.
The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing.
We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity.
Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
胃肠道炎症可能导致癌症的发生。二羰基亲电试剂，如异莱格（isoLGs），是在炎症反应中脂质过氧化产生的，可与含胺的大分子形成共价加合物。因此，我们试图确定二羰基亲电试剂在炎症相关致癌中的作用。
分析了从胃炎到癌前肠上皮化生的幽门螺杆菌感染患者、人胃类器官以及结肠炎和结肠炎相关癌（CAC）患者胃组织中异莱格加合物的形成。在作为幽门螺杆菌诱导致癌模型的 FVB/N 胰岛素-胃泌素（INS-GAS）转基因小鼠和蒙古沙土鼠以及作为 CAC 模型的 C57BL/6 小鼠中，确定了强效二羰基亲电试剂清除剂 5-乙基-2-羟苯甲胺（EtHOBA）对癌症发展的影响。用全外显子组测序评估 EtHOBA 对感染幽门螺杆菌的 INS-GAS 小鼠胃上皮细胞突变的影响。
我们发现，在胃炎和肠上皮化生患者以及感染幽门螺杆菌的人胃类器官的胃上皮细胞核中，异莱格加合物增加。EtHOBA 抑制了感染 INS-GAS 小鼠和沙土鼠的胃癌，并减轻了异莱格加合物、DNA 损伤和体细胞突变频率。此外，在结肠炎、结肠炎相关发育不良和 CAC 患者的组织以及用氧化偶氮甲烷-葡聚糖硫酸钠处理的 C57BL/6 小鼠的发育不良肿瘤中，异莱格加合物也升高。在该模型中，EtHOBA 显著减少了加合物形成、肿瘤发生和发育不良的严重程度。
二羰基亲电试剂代表了炎症和体细胞基因组改变之间的联系，因此是癌症化学预防的关键靶点。
