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

描述(申请人提供)：幽门螺杆菌是世界上分布最广泛的人类病原体之一，感染了超过50%的人口。这种病原体是导致胃癌的主要因素，而胃癌是世界上第二大癌症死亡原因。幽门螺杆菌可诱导胃上皮细胞产生巨噬细胞移动抑制因子，而巨噬细胞移动抑制因子的产生是许多肿瘤发生的重要因素。MIF的一个受体是CD74，我已经证明它在体内和体外都有高表达，并被幽门螺杆菌上调。CD74还被证明在多种癌症中高表达，并被研究为癌症和免疫疾病的治疗靶点。幽门螺杆菌上调CD74的表达以及诱导MIF的能力，以及MIF促进癌变的作用，这一发现导致了假设：幽门螺杆菌诱导胃上皮细胞产生MIF，MIF与表面表达的CD74结合，从而产生致癌信号。针对这一假说的具体目的是：目的1.研究幽门螺杆菌诱导胃上皮细胞MIF产生的机制，包括MIF产生的动力学、细菌因素和信号转导。目的2.确定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了与幽门螺杆菌感染相关的信号事件。CD74作为MIF在胃上皮细胞上的受体的作用将与MIF可能利用的任何其他受体的存在一起被检测。MIF结合的CD74调节幽门螺杆菌感染过程中常见的信号的能力也将被研究。目的3.探讨MIF与CD74结合对胃上皮细胞促癌信号转导及增殖的影响。将其与毒力菌、CAg缺失菌株、抗CD74封闭抗体和抗MIF中和抗体进行比较。我们将研究MIF对细胞周期动力学的影响。这些研究将对细胞信号和反应提供有价值的见解，这些信号和反应在炎症和胃癌的发展中都是至关重要的。

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.