TREFOIL BINDING PROTEINS IN GASTRIC CARCINOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胃癌是世界范围内死亡的主要原因，通常在幽门螺杆菌感染之前。对幽门螺杆菌在胃癌发生发展中的作用的认识为研究胃癌发生的分子和细胞事件以及发现新的胃癌生物标志物提供了新的机会。这些洞察力可能导致确定胃癌风险最高的患者，并具有预后和治疗应用。在第一个Cobre资金周期中，我们评估了Hp下调p27的机制和后果，获得了R01资金以继续下去。这一新的试验性建议建立在我们最近对幽门螺杆菌体内感染的胃上皮细胞转录组的分析基础上。我们利用激光捕获显微切割和基因芯片鉴定，选择了在幽门螺杆菌感染组织中表达显著降低的2个新的相关基因(胃动素[GKN]1和2)进行进一步的研究。我们之所以关注GKN1和GK2，是因为(I)胃动素2(GKN2)是幽门螺杆菌下调表达最多的基因，(Ii)最近有人报道在小型胃癌系列中胃动素1和2的表达降低，我们证实在很大一部分胃癌病例中缺失GKN1和GK2，以及(Iii)生物学上的合理性-GKN2与三叶因子家族蛋白相互作用，参与胃粘膜修复、幽门螺杆菌黏附和致癌。我们推测：(1)GKN1和GKN2受幽门螺杆菌的调控，可能是胃癌的抑制因子；(2)GKN1和GKN2的表达可能是胃癌的生物标志物。这些假说将通过(1)在体外和体内检测胃细胞中GKN1和GKN2的变化对细胞的影响，以及(2)在幽门螺杆菌感染患者的前瞻性临床研究和幽门螺杆菌诱导的胃癌小鼠模型中评估GKN1和GKN2作为胃癌易感性的生物标志物的实用性，来检验这些假说。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastric cancer, a major cause of mortality worldwide, is usually preceded by pylori infection. Recognition of H. pylori's role in gastric cancer development affords novel opportunities to study the molecular and cellular events of gastric carcinogenesis and discover novel gastric cancer biomarkers. These insights may lead to the identification of patients at highest gastric cancer risk, and have prognostic and therapeutic applications. In the first COBRE funding cycle, we evaluated the mechanisms and consequences of p27 down-regulation by H. pylori, garnering R01 funding to continue. This new pilot proposal builds upon our recent analysis of the gastric epithelial cell transcriptome of H. pylori infection in vivo. We used laster capture microdissection and gene chips identified, 2 novel related genes (gastrokine [GKN] 1 and 2) that were highly significantly decreased in expression in H. pylori infected tissues were selected for further study. Our focus on GKN1 and 2 is because (i) Gastrokine 2 (GKN2) was the gene whose expression was the most down-regulated by H. pylori, (ii) decreased expression of gastrokines 1 & 2 were recently reported in small gastric cancer series by others, and confirmed by us to be lost in a large proportion of cases in gastric cancer, and (iii) biological plausibility-GKN2 interacts with trefoil factor family proteins involved in gastric mucosal repair, H. pylori adherence and carcinogenesis. We hypothesize that (1) GKN1 and GKN2 are regulated by H. pylori and act as gastric cancer tumor suppressors: and (2) expression of GKN1 and GKN2 may serve as gastric cancer biomarkers. These hypotheses will be tested over 2 years by (1) examining the cellular effects of alterations in GKN1 and GKN2 in gastric cells in vitro and in vivo and (2) by evaluating the utility of GKN1 and GKN2 as biomarkers of gastric cancer susceptibility in a prospectively clinical study of H. pylori-infected patients and in a mouse model of H. pylori-induced gastric cancer.