Osburn William O, Karim Baktiar, Dolan Patrick M, Liu Guosheng, Yamamoto Masayuki, Huso David L, Kensler Thomas W
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD.
Int J Cancer. 2007 Nov 1;121(9):1883-1891. doi: 10.1002/ijc.22943.
Chronic inflammation has been associated with increased risk of developing cancer. The transcription factor NF-E2-related factor 2 (Nrf2) controls the expression of numerous antioxidative enzymes that have been shown to attenuate acute inflammation. The present study investigated the role of Nrf2 genotype in modulating inflammation-promoted colorectal tumorigenesis. Nrf2 wild-type (WT) and Nrf2-deficient (N0) mice were administered a single dose of azoxymethane followed by a 1-week dose of drinking water with or without 1% dextran sulfate sodium (DSS). Aberrant crypt foci were counted 3 weeks after the cessation of DSS treatment. DSS treatment significantly increased numbers of aberrant crypt foci in N0 mice, but not WT mice. The extent of inflammation over the course of DSS treatment was analyzed in both genotypes. Histological analysis of colon sections revealed that N0 mice had markedly increased inflammation and mucosal damage when compared to WT mice beginning on Day 6 of DSS treatment. Although similar levels of inflammatory and oxidative damage biomarkers were evident in colons from WT and N0 mice at the start of DSS treatment, increased colonic proinflammatory cytokine mRNA transcript levels, myeloperoxidase activity and 3-nitrotyrosine immunoreactivity were observed on Day 6 of DSS treatment in N0 mice, but not WT mice. Additionally, DSS treatment resulted in increased lipid peroxidation and loss of aconitase activity in N0 mice, but not WT mice, reflecting increased oxidative damage in colons from N0 mice. Taken together, these results clearly illustrate the role of Nrf2 in regulating an adaptive response that protects against early-phase inflammation-mediated tumorigenesis.
慢性炎症与患癌风险增加有关。转录因子核因子E2相关因子2（Nrf2）控制着众多抗氧化酶的表达，这些抗氧化酶已被证明可减轻急性炎症。本研究调查了Nrf2基因型在调节炎症促进的结直肠癌发生中的作用。给Nrf2野生型（WT）和Nrf2缺陷型（N0）小鼠单次注射氧化偶氮甲烷，随后给予含或不含1%硫酸葡聚糖钠（DSS）的饮用水，持续1周。在停止DSS治疗3周后计数异常隐窝病灶。DSS治疗显著增加了N0小鼠而非WT小鼠的异常隐窝病灶数量。分析了两种基因型在DSS治疗过程中的炎症程度。结肠切片的组织学分析显示，与WT小鼠相比，从DSS治疗第6天开始，N0小鼠的炎症和黏膜损伤明显增加。尽管在DSS治疗开始时，WT和N0小鼠结肠中炎症和氧化损伤生物标志物的水平相似，但在DSS治疗第6天，在N0小鼠而非WT小鼠中观察到结肠促炎细胞因子mRNA转录水平、髓过氧化物酶活性和3-硝基酪氨酸免疫反应性增加。此外，DSS治疗导致N0小鼠而非WT小鼠的脂质过氧化增加和乌头酸酶活性丧失，这反映了N0小鼠结肠中氧化损伤增加。综上所述，这些结果清楚地说明了Nrf2在调节一种适应性反应中的作用，这种反应可防止早期炎症介导的肿瘤发生。
