STAT3参与的正反馈环路在幽门螺杆菌致病中的机制研究

Helicobacter pylori (Hp) is an important pathogen that causes a wide range of gastroduodenal diseases. The primary feature of Hp infection is a chronic inflammatory infiltrate characterized by the release of proinflammatory cytokines such as cyclooxygenase-2 (COX-2) and interleukins (IL). However, the signaling pathway involved in Hp pathogenicity is not yet completely understood. Recently, our data show that Hp rapidly triggers STAT3 signaling in human gastric epithelial cells and human gastric cancer epithelial cells. Additionally, ChIP-on-chip suggests that STAT3 may modulate the transcriptional activity of proinflammatory cytokines, such as COX2, TGF-α/β and TNF. Therefore, all these data provide evidence that STAT3 may contribute to Hp pathogenesis. Unfortunately, the roles of STAT3 in Hp-associated gastric diseases remain unclear and the crosstalk between STAT3 and proinflammatory cytokines in the development and progression of gastric disorders remain to be clarified. Thus, this study were undertaken to assess the biological significance of STAT3 signaling in Hp pathogenicity and to explore the crosstalk between STAT3 and proinflammatory cytokines after H.pylori infection. Our aim is to further elucidate the mechanisms by which H.pylori exerts its pathogenic effects in the human stomach.

幽门螺杆菌Hp诱导的，以环氧合酶2（COX2）等炎症因子为基础的慢性炎症是Hp相关性疾病核心。但应答Hp的相关信号通路及信号转导步骤仍不清楚。本课题组近期发现，Hp可迅速激活正常胃粘膜细胞及胃癌细胞中STAT3；利用启动子芯片技术发现，转录因子STAT3可能调控众多炎症及肿瘤相关基因转录（如COX2、TGF、TNF）。据此我们设想STAT3通路可能参与Hp致病，STAT3与相关炎症因子间相互影响及调控。然而目前鲜有研究深入探讨STAT3通路在Hp致病中的作用；不清楚Hp诱导的相关炎症因子与STAT3间的调控关系及机制。本项目将以我们前期的重要发现为基础，深入研究 ①STAT3应答Hp刺激的信号转导机制；②阐释STAT3与Hp诱导的相关炎症因子间的相互表达调控关系及机制；③明确STAT3在Hp介导的炎症中的作用。旨在揭示STAT3信号在Hp致病中的意义，为临床Hp相关疾病的诊治提供新思路。

持续的幽门螺杆菌（HP）感染诱发胃炎、胃癌等疾病。然而，HP的致病机制仍未明了。本项目着重探讨了STAT3通路可能参与Hp致病，及其与COX-2相互调控并参与HP致病的机制。我们发现：体内及体外实验中HP可迅速激活STAT3通路，并诱导STAT3依赖的COX-2表达上调。在正常胃粘膜细胞及胃癌细胞中，STAT3可结合COX-2启动子，转录调控COX-2表达。另一方面，无论在基础状态还是在HP感染时，COX-2可调控IL-6/STAT3信号通路。因此，我们的实验证实：在基础状态及在HP感染时，STAT3与COX-2间存在正反馈环路，此环路参与HP致病。此外，免疫组化实验发现HP感染的胃炎组织中，激活的STAT3（pSTAT3tyr705）表达明显高于非HP感染的胃炎组织。另外，胃炎组织及胃癌组织中STAT3/pSTAT3tyr705表达与COX-2间存在正相关；高表达pSTAT3tyr705与肠化生及异型增生相关，提示pSTAT3tyr705可能对胃癌的早诊有意义。综上所述，本研究首次发现STAT3与COX-2间存在正反馈环路，且此环路参与HP致病。该研究为揭示HP致病机制、临床Hp相关疾病的诊治提供新思路。