Role of IL-17A in the development of colitis-associated cancer
Role of IL-17A in the development of colitis-associated cancer
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DOI：
10.1093/carcin/bgs106
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发表时间：
2012-04-01
期刊：
影响因子：
4.7
通讯作者：
Kim, Ho-Youn
中科院分区：
文献类型：
--
作者：
Hyun, Yil Sik;Han, Dong Soo;Kim, Ho-Youn
炎症与结肠癌之间的密切关系已被广泛接受，而白介素17A在控制结肠炎中起着重要作用。然而，IL-17A在结肠炎相关性癌症(CAC)中的作用尚未得到证实。本研究旨在利用IL-17A缺陷小鼠在实验性CAC模型中确定IL-17A在肿瘤发生中的作用。给IL-17A缺陷小鼠和C57BL/6(野生型，WT)小鼠注射12.5 mg/kg偶氮甲烷，然后三轮1.7%葡聚糖硫酸钠暴露诱导结肠炎，均可诱发CAC。在研究开始后第63天，处死小鼠。观察大鼠结肠炎症、增殖和肿瘤形成情况。与WT小鼠相比，IL-17A缺陷小鼠的肿瘤数目(1.43比5.80；P=0.02)和平均肿瘤大小(1.17比3.58 mm；P=0.01)显著减少。此外，IL-17A缺陷小鼠的炎症和增殖评分明显低于WT小鼠。在炎性介质的分析中，IL-17A缺陷小鼠的IL-6、干扰素-γ、肿瘤坏死因子-α和IL-17A显著低于WT小鼠。在蛋白质印迹分析中，p-STAT3、细胞周期蛋白D1、细胞周期蛋白依赖性激酶2、细胞周期蛋白E、糖原合成酶3-β和p-Akt在IL-17A缺陷小鼠中表达下调。P-STAT3、Ki-67和β-catenin免疫组织化学染色显示，IL-17A缺陷小鼠的染色细胞数低于WT小鼠。IL-17A消融可显著降低CAC的致瘤性，因此可能在慢性结肠炎中发挥重要作用。
A close relationship between inflammation and colon cancer has been widely accepted, and interleukin (IL)-17A plays an important role in controlling colonic inflammation. However, the role of IL-17A has not yet been validated in colitis-associated cancer (CAC). This study aims to identify the effects of IL-17A in tumorigenesis utilizing IL-17A-deficient mice in an experimental CAC model. CAC was induced in both the IL-17A-deficient and the C57BL/6 (wild-type, WT) mice by injection of 12.5 mg/kg azoxymethane followed by three rounds of 1.7% dextran sodium sulfate exposure to elicit colitis. On day 63 after the start of the study, mice were sacrificed. Colonic inflammation, proliferation and tumorigenesis were evaluated. Tumor numbers per mouse (1.43 versus 5.80; P = 0.02) and mean tumor size (1.17 versus 3.58 mm; P = 0.01) were significantly decreased in IL-17A-deficient mice compared with WT mice. Furthermore, the inflammation and the proliferation scores of IL-17A-deficient mice were significantly lower than WT mice. In the analysis of inflammatory mediators, IL-6, interferon-gamma, tumor necrosis factor-alpha and IL-17A were markedly decreased in IL-17A-deficient mice compared with WT mice. In the western blot analysis, p-STAT3, cyclin D1, cyclin-dependent kinase 2, cyclin E, Glycogen synthase kinase 3-beta and p-Akt were downregulated in IL-17A-deficient mice. Immunohistochemical staining with p-STAT3, Ki-67 and beta-catenin revealed lower number of stained cells in IL-17A-deficient mice compared with WT mice. IL-17A ablation significantly decreases CAC tumorigenesis and thus may play an important role associated with chronic colitis.