Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice.
Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice.
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DOI：
10.1002/mc.20427
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发表时间：
2008-08
影响因子：
4.6
通讯作者：
Yang, Guang-Yu
中科院分区：
文献类型：
--
作者：
Liao, Jie;Seril, Darren N.;Lu, Gary G.;Zhang, Meng;Toyokuni, Shinya;Yang, Allison L.;Yang, Guang-Yu
Ogg1 DNA 修复酶可识别并切除 GC 碱基对中氧化应激引起的 8-羟基脱氧鸟苷 (8-OHdG)。 Ogg1 基因敲除小鼠表型正常，但核和线粒体 DNA 中 8-OHdG 水平升高，并且突变发生和自发性肺肿瘤以及紫外线诱导的皮肤肿瘤中度升高。为了阐明炎症引起的氧化应激在致癌过程中的机制作用，我们使用葡聚糖硫酸钠 (DSS) 诱导的 UC 模型（不使用致癌物）研究了 Ogg1 敲除小鼠中慢性溃疡性结肠炎 (UC) 诱导的癌症的发展。 Ogg1 (−/−)、Ogg1 (+/-) 和野生型 C57BL/6 小鼠接受长期、循环 DSS 治疗以诱导慢性 UC 和癌变。野生型C57BL/6对照小鼠经过15个周期的DSS治疗后，结直肠腺癌发生率为24.1%（7/29小鼠），肿瘤体积为27.9±5.2mm3。 Ogg1 (−/−) 小鼠的结肠腺癌发展显着增加，肿瘤发生率为 57.1%（21 只小鼠中的 12 只，P < 0.05），肿瘤体积为 35.1 ± 6.1 mm3。 Ogg1 小鼠 (+/-) 还表现出结肠中肿瘤发育显着增加，肿瘤发生率为 50.0%（13/26 小鼠），肿瘤体积为 29.1 ± 7.2 mm3。组织病理学分析显示，结直肠肿瘤为分化良好的管状腺癌或粘液癌，邻近结肠粘膜呈轻至中度慢性UC。使用免疫组织化学方法，Ogg1 (−/−) 和 (+/-) 小鼠在 UC 区域表现出与 Ogg1 (+/+) 小鼠相似的巨噬细胞数量和染色强度，但 8-OHdG 阳性炎症细胞和上皮细胞的数量和染色强度显着增加。这些结果为炎症引起的氧化应激、DNA 修复酶 Ogg1 和癌发生之间的关系提供了重要证据。
Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (−/−), Ogg1 (+/−), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 ± 5.2 mm3. Ogg1 (−/−) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 ± 6.1 mm3. Ogg1 mice (+/−) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 ± 7.2 mm3. Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (−/−) and (+/−) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis.
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影响因子：
4.7
作者：
Seril, DN;Liao, J;Yang, GY
通讯作者：
Yang, GY
影响因子：
4.7
作者：
Cooper, HS;Murthy, S;Flanigan, A
通讯作者：
Flanigan, A
影响因子：
3
作者：
HEIMANN, TM;OH, SC;GREENSTEIN, AJ
通讯作者：
GREENSTEIN, AJ
DOI：
10.1073/pnas.87.4.1620
发表时间：
1990-02-01
影响因子：
11.1
作者：
BECKMAN, JS;BECKMAN, TW;FREEMAN, BA
通讯作者：
FREEMAN, BA
影响因子：
3.1
作者：
Seril, DN;Liao, J;Yang, GY
通讯作者：
Yang, GY