Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis
Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis
复制标题
AEG-1 诱导的不受控制的炎症会促进胃癌发生并导致预后不良。
DOI：
10.1158/0008-5472.can-14-0968
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Xu, Jianbo
中科院分区：
文献类型：
--
作者：
Li, Guanghua;Wang, Zhao;Xu, Jianbo
胃癌是世界范围内癌症相关死亡的最常见原因之一。幽门螺杆菌感染在胃癌的发生、发展中起重要作用。星形胶质细胞升高基因-1（AEG-1）在胃癌组织中的表达增加，从而有助于炎症反应。我们研究了AEG-1是否以及如何调节胃癌细胞中的促炎信号。本研究采用人胃癌细胞株和裸鼠模型，通过免疫组化方法检测AEG-1在TLR 4/NF-κ B（nuclear factor-kappa B，NF-κ B B）信号通路中的表达，并比较AEG-1及其相关蛋白在93例胃癌组织中的表达。在人胃癌细胞中，AEG-1和TLR 4均可被脂多糖（LPS）诱导表达。AEG-1通过LPS-TLR 4信号传导上调，进而促进NF-κ B p65亚基的核转位。与此同时，AEG-1过表达降低了细胞因子信号传导抑制因子（SOCS）蛋白SOCS-1的水平，SOCS-1是TLR 4通路的负调节因子。此外，移植AEG-1/TLR 4表达细胞的裸鼠显示出比对照动物更大的肿瘤体积。在胃癌患者中，AEG-1的表达与TLR 4、SOCS-1和NF-κ B的表达相关，并且在肿瘤中的表达高于非癌旁组织。AEG-1和TLR 4同时表达的胃癌患者的总体生存率较差。我们的研究结果表明AEG-1可以通过TLR 4/NF-κ B信号相关的正反馈机制促进胃癌的进展，从而为炎症在癌症进展中的作用提供了新的机制解释。(C)2014年AACR。
Gastric cancer is one of the most common causes of cancer-related death worldwide. Helicobacter pylori infection plays an important role in the development and progression of gastric cancer. The expression of astrocyte-elevated gene-1 (AEG-1) is increased in gastric cancer tissues, thereby contributing to the inflammatory response. We investigated whether and how AEG-1 regulated proinflammatory signaling in gastric cancer cells. We used human gastric cancer cell lines and athymic nude mice to investigate the role of AEG-1 in the regulation of the TLR4/nuclear factor-kappa B (NF-kappa B) signaling pathway and cancer invasion and compared the expression of AEG-1 and related proteins in 93 patients with gastric cancer by immunohistochemistry. In human gastric cancer cells, both AEG-1 and TLR4 could be induced by lipopolysaccharide (LPS) stimulation. AEG-1 was upregulated via LPS-TLR4 signaling and in turn promoted nuclear translocation of the NF-kappa B p65 subunit. At the same time, AEG-1 overexpression decreased the levels of suppressor of cytokine signaling (SOCS) protein SOCS-1, a negative regulator of the TLR4 pathway. Furthermore, nude mice engrafted with AEG-1/TLR4-expressing cells demonstrated larger tumor volumes than control animals. In patients with gastric cancer, the expression of AEG-1 correlated with that of TLR4, SOCS-1, and NF-kappa B and was higher in tumors compared with noncancerous adjacent tissues. Overall survival in patients with gastric cancer with simultaneous expression of AEG-1 and TLR4 was poor. Our results demonstrate that AEG-1 can promote gastric cancer progression by a positive feedback TLR4/NF-kappa B signaling-related mechanism, thus providing new mechanistic explanation for the role of inflammation in cancer progression. (C) 2014 AACR.