TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells
TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells
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DOI：
10.1002/ijc.23484
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Fujiki, Hirota
中科院分区：
文献类型：
--
作者：
Sujanuma, Masami;Yamaguchi, Kensei;Fujiki, Hirota
tnf - α诱导蛋白（Tip α）由幽门螺杆菌（Helicobacter pylori， H. pylori）分泌：它是tnf - α和chentokine基因的有效诱导剂，通过NF-kappa B活化介导，并在Bhas 42细胞中诱导促肿瘤活性。为了研究带有Tip α的幽门螺杆菌的致癌机制，我们首先研究了Tip α如何作用于胃上皮细胞。我们发现荧光-Tip α以剂量和温度依赖的方式特异性结合并进入细胞，而Tip α的缺失突变体（del-Tip α）是一种非活性形式，既不结合也不进入细胞，这表明存在特定的结合分子。Tip α的诱变分析表明，Tip α具有二硫键的二聚体是特异性结合和诱导tnf - α基因表达所必需的。共聚焦激光扫描显微镜下可见核内有部分Tipa，但未见del-Tip α的存在，提示有活性形式的Tip α可穿透细胞核，可能参与诱导tnf - α基因的表达。对28株临床分离株的Tip α产生和分泌的检测显示，胃癌患者的幽门螺杆菌分泌的Tip α量明显高于慢性胃炎患者的幽门螺杆菌，提示Tip α是人类胃中幽门螺杆菌炎症和癌症微环境的重要因素。Tip α是一种新的幽门螺杆菌致癌因子，可以通过特定的结合分子进入细胞核，其作用机制与CagA完全不同。(C) 2008 Wiley-Liss, Inc。
TNF-alpha inducing protein (Tip alpha) is secreted from Helicobacter pylori (H. pylori): it is a potent inducer of TNF-alpha and chentokine genes, mediated through NF-kappa B activation, and it also induces tumor-promoting activity in Bhas 42 cells. To investigate the carcinogenic mechanisms of H. pylori with Tip alpha, we first examined how Tip alpha acts on gastric epithelial cells. We found that fluorescent-Tip alpha specifically bound to, and then entered, the cells in a dose- and temperature-dependent manner, whereas deletion mutant of Tip alpha (del-Tip alpha), an inactive form, neither bound to nor entered the cells, suggesting the presence of a specific binding molecule. Mutagenesis analysis of Tip alpha revealed that a dimer formation of Tip alpha with a disulfide bond is required for both specific binding and induction of TNF-alpha gene expression. A confocal laser scanning microscope revealed some Tipa in the nuclei, but del-Tip alpha was not present, which indicated that an active form of Tip alpha can penetrate the nucleus and may be involved in the induction of TNF-alpha gene expression. Examination of Tip alpha production and secretion in 28 clinical isolates revealed that H. pylori obtained from gastric cancer patients secreted Tip alpha in significantly higher amounts than did H. pylori from patients with chronic gastritis, suggesting that Tip alpha is an essential factor in H. pylori inflammation and cancer microenvironment in the human stomach. Tip alpha is thus a new carcinogenic factor of H. pylori that can enter the nucleus through a specific binding molecule, and its mechanism of action is completely different from that of CagA. (C) 2008 Wiley-Liss, Inc.