Potential Role of H. Pylori-induced MIF in Gastric Cancer

描述（由申请人提供）：幽门螺杆菌是世界上最广泛的人类病原体之一，感染超过50%的人口。这种病原体是胃癌的主要贡献者，胃癌是世界上癌症死亡的第二大原因。H.幽门螺杆菌诱导胃上皮细胞产生巨噬细胞移动抑制因子（MIF），并且MIF的产生是许多癌症中的重要因素。MIF的受体是CD74，我已经证明它在体内和体外都高度表达，并被H.幽门。CD74也已被证明在多种癌症中高度表达，并且正在作为癌症和免疫疾病的治疗靶点进行研究。发现H. pylori上调CD 74，沿着H. pylori诱导MIF，并且MIF在促进致癌作用中的作用导致以下假设：幽门螺杆菌诱导胃上皮细胞产生MIF，其结合表面表达的CD74，导致促致癌信号传导。解决这一假设的具体目标是：目的1。探讨H.幽门螺杆菌诱导的胃上皮细胞MIF产生，其中将评估MIF产生中涉及的动力学、细菌因素和信号传导。AIM 2.目的：探讨CD74在MIF与胃上皮细胞相互作用中的作用，以及这种结合是否诱导与H.幽门感染将沿着检查CD 74作为胃上皮细胞上MIF受体的作用以及MIF可能利用的任何其它受体的存在。MIF结合的CD74调节信号传导的能力通常在H.还将研究幽门螺杆菌感染。AIM 3.探讨MIF与CD74结合对胃上皮细胞促癌信号传导和增殖的作用。将与毒性细菌、cag缺失菌株、抗CD74阻断抗体和抗MIF中和抗体比较增殖和凋亡的动力学。将检查MIF对细胞周期动力学的影响。这些研究将为细胞信号传导和反应提供有价值的见解，这些信号传导和反应在炎症和胃癌的发展中至关重要。

DESCRIPTION (provided by applicant): Helicobacter pylori is one of the world's most widespread human pathogens, infecting more than 50% of the population. This pathogen is the major contributor to gastric cancer, which is the second leading cause of cancer deaths in the world. H. pylori induces macrophage migration inhibitory factor (MIF) production from gastric epithelial cells, and MIF production is an important factor in many cancers. A receptor for MIF is CD74, which I have shown to be highly expressed both in vivo and in vitro, and is upregulated by H. pylori. CD74 has also been shown to be highly expressed in a variety of cancers and is being studied as a therapeutic target in both cancer and immunologic diseases. The finding that H. pylori upregulates CD74, along with the ability of H. pylori to induce MIF, and the role MIF plays promoting carcinogenesis led to the hypothesis that: Helicobacter pylori induces gastric epithelial cell production of MIF, which binds to surface-expressed CD74 resulting in pro-carcinogenic signaling. The specific aims to address this hypothesis are: AIM 1. To characterize the mechanisms involved in H. pylori-induced gastric epithelial cell MIF production where the kinetics, the bacterial factors, and the signaling involved in MIF production will be assessed. AIM 2. To determine the role of CD74 in the interaction of MIF with gastric epithelial cells and whether this binding induces signaling events associated with H. pylori infection. The role of CD74 as the receptor for MIF on gastric epithelial cells will be examined along with the presence of any other receptors MIF may utilize. The ability of MIF-bound CD74 to modulate signaling typically seen during H. pylori infection will also be investigated. AIM 3. To determine the role of MIF binding to CD74 on gastric epithelial cell pro-carcinogenic signaling and proliferation. The kinetics of proliferation and apoptosis will be compared with virulent bacteria, strains with deleted cag, anti-CD74 blocking antibodies, and anti-MIF neutralizing antibodies. The effects of MIF on cell cycle kinetics will be examined. These studies will provide valuable insight into cell signaling and responses that are crucial in both inflammation and the development of gastric cancer.