Reduced MicroRNA-218 Expression Is Associated With High Nuclear Factor kappa B Activation in Gastric Cancer
Reduced MicroRNA-218 Expression Is Associated With High Nuclear Factor kappa B Activation in Gastric Cancer
复制标题
microRNA-218 表达减少与胃癌中核因子 kappa B 的高激活相关
DOI：
10.1002/cncr.24743
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发表时间：
2010-01-01
期刊：
影响因子：
6.2
通讯作者：
Lu, Hong
中科院分区：
文献类型：
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作者：
Gao, Caiping;Zhang, Zhiyu;Lu, Hong
背景：据报道，microRNAs(MiRs)的低表达在胃癌的发生中起重要作用。大规模的基因芯片检测表明，miR-218在胃癌中的表达显著下调。在人乳头瘤病毒阳性细胞系、宫颈病变和宫颈癌组织以及吸烟者的支气管呼吸道上皮中，MIR-218也特别降低。然而，它在肿瘤发生中的作用尚不清楚，尤其是在幽门螺杆菌(H.Pylori)相关的胃癌中。方法：应用TaqMan实时定量聚合酶链式反应技术检测20例非贲门癌组织、10例幽门螺杆菌感染的正常胃组织和8例未感染的正常胃组织以及人胃上皮癌细胞株AGS中miR-218的表达水平。用前miR-218和抗miR-218抑制剂检测miR-218表达对细胞增殖和凋亡的影响。荧光素酶报告实验用于检测潜在的靶基因和相关途径。结果：MIR-218在胃癌组织、幽门螺杆菌感染的胃粘膜和幽门螺杆菌感染的AGS细胞中的表达显著降低。在体外，miR-218过表达可抑制细胞增殖，增加细胞凋亡率。表皮生长因子受体共扩增和过表达蛋白(ECOP)是miR-218的直接靶点，它调节核因子-kappa B(NF-kappa B)的转录活性，并与细胞凋亡反应相关。此外，miR-218的过表达也抑制了核因子-kappa B的转录激活和环氧合酶-2的转录。结论：幽门螺杆菌感染导致miR-218的表达下降。MiR-218的下调有可能通过失去对其靶点的控制而增加肿瘤的发生，这可能与幽门螺杆菌感染导致的核因子-kappa B的高转录活性有关。癌症2010；116：41-9。(C)2010年美国癌症协会。
BACKGROUND: Poor expression of microRNAs (miRs) reportedly plays an important role in gastric carcinogenesis. Large-scale microarray assays have indicated that there is significant down-regulation of miR-218 in gastric cancer. miR-218 also was decreased specifically in human papillomavirus-positive cell lines, cervical lesions, and cervical cancer tissues and in bronchial airway epithelium in smokers. However, its role in carcinogenesis remains unclear, especially in Helicobacter pylori (H. pylori)-associated gastric cancer. METHODS: miR-218 levels were evaluated in 20 noncardia gastric cancer tissues, in 10 H. pylori-infected and 8 uninfected normal gastric biopsies, and in the human gastric epithelial cancer cell line AGS using TaqMan quantitative real-time polymerase chain reaction analysis. Pre-miR-218 and anti-miR-218 inhibitors were used to examine the effects of miR-218 expression on cell proliferation and apoptosis. A luciferase reporter assay was used to examine the potential target genes and related pathways. RESULTS: miR-218 expression was reduced significantly in gastric cancer tissues, in H. pylori-infected gastric mucosa, and in H. pylori-infected AGS cells. Overexpression of miR-218 inhibited cell proliferation and increased apoptosis in vitro. Epidermal growth factor receptor-coamplified and overexpressed protein (ECOP), which regulates nuclear factor kappa B (NF-kappa B) transcriptional activity and is associated with apoptotic response, was a direct target of miR-218. Overexpression of miR-218 also inhibited NF-kappa B transcriptional activation and transcription of cyclooxygenase -2, a proliferative gene regulated by NF-kappa B. CONCLUSIONS: H, pylori infection resulted in a decrease in miR-218 expression. The down-regulation of miR-218 has the potential to increase carcinogenesis by losing control of its targets, and it may be correlated with the high transcriptional activity of NF-kappa B that results from H. pylori infection. Cancer 2010;116:41-9. (C) 2010 American Cancer Society.