EGFR Activation and Polyamines in H.Pylori-Induced Gastric Cancer

幽门螺杆菌感染了半个世界，是胃癌的主要原因，胃癌是全球癌症死亡的第二大原因。然而，普遍根除是不可行的，迫切需要查明患癌症的高危人群，并制定新的干预战略。我们已经直接暗示了表皮生长因子受体（pEGFR）的磷酸化和精胺氧化酶（SMO）的诱导在对H. pylori感染。我们发表的和初步的数据表明，氧化的多胺精胺的SMO的结果在生成的H2 O2，这是在感染的胃上皮细胞的DNA损伤的原因，和pEGFR是所需的SMO表达和介导的细胞亚群的产生与SMO驱动的DNA损伤，是抗凋亡。这些事件发生在条件永生化胃上皮细胞和胃癌发生的体内模型（INS-GAS小鼠和蒙古沙鼠）中，并且人体组织表现出SMO和DNA损伤的强相关性。抑制多胺合成或SMO可减少沙鼠的胃发育不良和胃癌。我们的磷酸化蛋白质组学和人类组织微阵列研究表明，除了SMO之外，EGFR和ErbB 2信号传导也参与了胃癌发生的启动。此外，尽管pEGFR显著增加，但体外和体内多胺的消耗减少了氧化性DNA损伤和癌。我们的假设是多胺决定了EGFR磷酸化对H。幽门诱导的炎症、DNA损伤和胃癌发生。我们的具体目标是在H中确定以下内容。幽门螺杆菌诱导的胃癌发生：1）EGFR反式激活和抗凋亡细胞的作用; 2）pEGFR的有害作用是否需要多胺; 3）所涉及的EGFR信号传导的阳性和阴性调节剂。这些研究将纳入独特的体外和离体模型，如胃类器官，以及在本PPG中采用的小鼠和沙鼠胃发育不良和癌的经证实模型，以实现这些目标。我们将受益于与项目1和3的持续密切合作，包括H。pylori突变菌株和来自我们不同动物系统的输出菌株，分享与信号传导相关的样本和专业知识，以及我们对SMO诱导的氧化应激和DNA损伤的分析。该项目将利用HIBEROLOGY核心A的卓越质量为目标1-3和蛋白质组学核心8为目标3，并将受益于独特的强大的环境，在范德比尔特的研究H。幽门螺杆菌和胃癌。

Helicobacter pylori infects half the world and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. However, universal eradication is not feasible and there is a strong need to identify persons at high risk for cancer development and develop new strategies for intervention. We have directly implicated phosphorylation of the epidermal growth factor receptor (pEGFR) and induction of spermine oxidase (SMO) in the aberrant signaling response to H. pylori in gastric epithelial cells. Our published and preliminary data show that oxidation of the polyamine spermine by SMO results in generation of H2 02 that is the cause of DNA damage in infected gastric epithelial cells, and that pEGFR is required for SMO expression and mediates the generation of a subpopulation of cells with SMO-driven DNA damage that are resistant to apoptosis. These events occur in conditionally immortalized gastric epithelial cells and in in vivo models of gastric carcinogenesis (INS-GAS mice and Mongolian gerbils), and human tissues exhibit a strong correlation of SMO and DNA damage. Inhibition of polyamine synthesis or SMO reduces gastric dysplasia and carcinoma in gerbils. Our phosphoproteomics and human tissue microarray studies have implicated EGFR and ErbB2 signaling in addition to SMO in the initiation of gastric carcinogenesis. Additionally, depletion of polyamines in vitro and in vivo reduces oxidative DNA damage and carcinoma despite substantially increasing pEGFR. Our hypothesis is that polyamines determine the effects of EGFR phosphorylation on H. pylori-induced inflammation, DNA damage, and gastric carcinogenesis. Our Specific Aims are to determine the following in H. pylori-induced gastric carcinogenesis: 1) the role of EGFR transactivation and apoptosis-resistant cells; 2) if polyamines are required for the deleterious effects of pEGFR; and 3) the positive and negative regulators of EGFR signaling that are involved. These studies will incorporate unique in vitro and ex vivo models such as gastric organoids, and proven models of gastric dysplasia and carcinoma in mice and gerbils that are employed across this PPG to pursue these aims. We will benefit from continued close collaborations with Projects 1 and 3 that will include exchange of H. pylori mutant strains and output strains from our different animals systems, sharing of samples and expertise related to signaling, and our analysis of SMO-induced oxidative stress and DNA damage. This project will leverage the exceptional quality of Histopathology Core A for Aims 1-3 and Proteomics Core 8 for Aim 3, and will benefit from the uniquely strong environment at Vanderbilt for studies of H. pylori and gastric cancer.