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。这种病原体是导致胃癌的主要原因，而胃癌是世界上第二大癌症死亡原因。幽门螺杆菌诱导胃上皮细胞产生巨噬细胞迁移抑制因子（MIF），而MIF的产生是许多癌症的重要因素。MIF的一个受体是CD74，我已经证明它在体内和体外都是高表达的，并且被幽门螺杆菌上调。CD74也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。幽门螺杆菌上调CD74的发现，以及幽门螺杆菌诱导MIF的能力，以及MIF在促进癌变中的作用，导致了这样的假设：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，产生促癌信号。解决这一假设的具体目标是：目标1。为了描述幽门螺杆菌诱导胃上皮细胞产生MIF的机制，将评估MIF产生的动力学、细菌因素和信号传导。目标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与幽门螺杆菌感染相关的信号事件。CD74作为MIF受体在胃上皮细胞上的作用将与MIF可能利用的任何其他受体的存在一起进行研究。mif结合的CD74调节幽门螺杆菌感染过程中典型信号的能力也将被研究。目标3。探讨MIF结合CD74对胃上皮细胞前致癌信号传导和增殖的作用。增殖和凋亡动力学将与毒性细菌、缺失cag的菌株、抗cd74阻断抗体和抗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。这些研究将为研究在炎症和胃癌发展中至关重要的细胞信号传导和反应提供有价值的见解。

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.