DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice
DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice
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DOI：
10.1172/jci35073
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发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Samson, Leona D.
中科院分区：
文献类型：
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作者：
Meira, Lisiane B.;Bugni, James M.;Samson, Leona D.
慢性炎症增加癌症风险。虽然很明显，由炎性细胞因子引起的细胞信号传导促进肿瘤发展，但由炎症相关的活性氧和氮物质（RONS）引起的DNA损伤产生对肿瘤发展的影响尚未直接测试。RONS诱导DNA损伤，其可被烷基腺嘌呤DNA糖基化酶（Aag）识别以启动碱基切除修复。通过在饮用水中重复给予葡聚糖硫酸钠，使用发作性炎症性肠病的小鼠模型，我们表明Aag介导的DNA修复可预防结肠上皮损伤并降低葡聚糖硫酸钠诱导的结肠肿瘤发生的严重程度。重要的是，预期由RONS诱导并由Aag识别的DNA碱基损伤在刺激结肠炎症后在Aag缺陷动物中积累到更高水平。最后，作为这种效果的一般性的测试，我们表明，Aag缺陷的动物显示更严重的胃病变，慢性感染幽门螺杆菌后胃癌的前体。这些数据表明，在慢性炎症过程中由RONS形成的DNA损伤的修复对于防止结肠癌发生是重要的。
Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithehal damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.