A positive feedback loop between STAT3 and cyclooxygenase-2 gene may contribute to Helicobacter pylori-associated human gastric tumorigenesis
A positive feedback loop between STAT3 and cyclooxygenase-2 gene may contribute to Helicobacter pylori-associated human gastric tumorigenesis
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STAT3和环氧合酶2基因之间的正反馈环可能有助于幽门螺杆菌相关的人胃肿瘤发生
DOI：
10.1002/ijc.28539
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发表时间：
2014-05-01
影响因子：
6.4
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
--
作者：
Xiong, Hua;Du, Wan;Fang, Jing-Yuan
幽门螺杆菌(Hp)的持续感染可导致慢性胃炎和胃癌等胃病。然而，这种致癌细菌的致病机制尚未完全阐明。在此，我们报道了幽门螺杆菌在体外和体内快速触发STAT3信号转导和诱导STAT3依赖的COX-2表达。STAT3通过与COX-2启动子结合并增加其活性来上调COX-2。在基础状态下和幽门螺杆菌感染期间，COX-2反过来调节IL-6/STAT3信号转导。这些结果表明，在基础状态和幽门螺杆菌感染状态下，STAT3和COX-2之间存在正反馈环。免疫组织化学染色显示幽门螺杆菌阳性胃炎组织中pSTAT3(Tyr705)的表达水平明显高于幽门螺杆菌阴性胃炎组织。高水平的pSTAT3(Tyr705)与肠化生和异型增生相关，提示pSTAT3(Tyr705)可能有助于早期检测胃肿瘤的发生。此外，胃炎和胃癌组织中STAT3/pSTAT3(Tyr705)水平与COX-2表达呈显著正相关。总之，这些发现为幽门螺杆菌致病过程中STAT3信号和COX-2之间的正反馈回路提供了新的证据，并可能为胃癌的早期发现和有效治疗提供新的途径。
Persistent infection with Helicobacter pylori (H. pylori) contributes to gastric diseases including chronic gastritis and gastric cancer. However, the pathogenesis of this carcinogenic bacterium has not been completely elucidated. Here, we report that H. pylori rapidly triggers STAT3 signaling and induces STAT3-dependent COX-2 expression both in vitro and in vivo. STAT3 upregulats COX-2 by binding to and increasing the activity of COX-2 promoter. COX-2 in turn regulates IL-6/STAT3 signaling under basal conditions and during H. pylori infection. These findings suggest that a positive feedback loop between STAT3 and COX-2 exists in the basal condition and H. pylori infectious condition. Immunohistochemical staining revealed that H. pylori-positive gastritis tissues exhibited markedly higher levels of pSTAT3(Tyr705) than H. pylori-negative ones. High pSTAT3(Tyr705) levels are correlated with intestinal metaplasia and dysplasia, suggesting pSTAT3(Tyr705) may be useful in the early detection of gastric tumorigenesis. Additionally, a strong positive correlation between STAT3/pSTAT3(Tyr705) levels and COX-2 expression was identified in gastritis and gastric cancer tissues. Together, these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H. pylori pathogenesis and may lead to new approaches for early detection and effective therapy of gastric cancer.