Polyamine Dysregulation in the Gastric Epithelium during Helicobacter pylori Infection and its Impact on Gastric Carcinogenesis

项目总结 幽门螺杆菌在世界上约50%的人口的胃部定植，是已知的最大风险 导致胃癌的因素是癌症相关死亡的第四大常见原因。主机故障 控制感染的反应会导致持续的炎症，这会从 慢性胃炎通过组织学“科雷亚级联”导致1-3%的胃癌 被感染了。由于抗生素耐药性，以及抗生素治疗在减少癌症方面可能无效 风险一旦出现癌前病变，我们需要开发新的治疗策略来限制进展。 到异型增生和癌症。我们的实验室研究了多胺、腐胺、亚精胺和 精胺在胃炎症和癌变中的作用腐胺依次转化为亚精胺，并 精胺，被精胺氧化酶(SMOX)反向转化为亚精胺。我们已经证明了SMOX 在感染幽门螺杆菌的人和小鼠胃组织中表达升高。此外，受感染的 C57BL/6 Smox-/-小鼠表现出精胺水平降低，胃炎和致癌信号减少 与野生型小鼠相比。使用FVB/N INS-GAS易发展为胃不典型增生和粘膜内的小鼠 幽门螺杆菌感染的Smox-/-小鼠表现出显著的幽门螺杆菌感染。 胃粘膜内癌的缩小和异型增生的程度。SMOX产生的精胺分解代谢 3-氨基丙醇，它可以自发形成丙烯醛，这是一种有潜力的反应性亲电醛 破坏DNA和蛋白质。我们的初步发现表明，在胃组织中产生了丙烯醛。 幽门螺杆菌感染的FVB/N INS-GAS小鼠，在Smox-/-FVB/N INS-GAS小鼠中显著降低。 此外，亚精胺是合成亚精氨酸的重要底物，亚精胺是一种独特的氨基酸，只有 在真核细胞翻译起始因子5A(EIF5A)中发现的，通过脱氧亚硫氨酸酶的作用 合酶(DHPs)。我们最近对人胃类器官的研究表明，高苏化的EIF5A可以诱导 幽门螺杆菌感染的水平，用该途径的化学抑制剂消融。蛋白质组学分析 在这些有机化合物上，暗示低效作用是肿瘤发生的关键途径。总而言之，我们 幽门螺杆菌感染的胃上皮细胞SMOX活性引起的多胺失调 以产生亚精胺和丙烯醛，并上调激素化途径，导致增加 有患上胃癌的风险。我们的具体目标是确定：1)SMOX活性在胃中的作用 致癌作用，包括亚精胺、精胺和丙烯醛对FVB/N INS-GAS小鼠的影响。2)如果亚精胺 在人类研究中，SMOX产生的SMOX通过过度刺激促进了胃癌的发生 胃类器官和上皮特异性DHPs缺失的小鼠。这项建议旨在澄清 SMOX诱导胃病进展的机制，从而确定新的靶向途径 为了治疗的好处，同时为我未来的首席调查员职业生涯提供理想的培训。

PROJECT SUMMARY Helicobacter pylori colonizes the stomach of about 50% of the world’s population and is the strongest known risk factor for developing gastric cancer, the fourth most common cause of cancer related deaths. Failure of the host response to control the infection leads to persistent inflammation, which initiates disease progression from chronic gastritis through a histological “Correa Cascade” that results in gastric carcinoma in 1-3% of all those infected. Due to antibiotic resistance, and the fact that antibiotic treatment may not be effective in reducing cancer risk once precancerous lesions are present, we need to develop new therapeutic strategies to limit progression to dysplasia and carcinoma. Our lab investigates the role of the polyamines, putrescine, spermidine, and spermine in gastric inflammation and carcinogenesis. Putrescine is sequentially converted to spermidine and spermine, which is back-converted to spermidine by spermine oxidase (SMOX). We have shown that SMOX expression is elevated in human and mouse gastric tissues infected with H. pylori. Furthermore, infected C57BL/6 Smox–/– mice exhibit depleted spermidine levels, and a decrease in gastritis and carcinogenic signaling compared to wild-type mice. Using FVB/N INS-GAS mice prone to developing gastric dysplasia and intramucosal carcinoma with H. pylori infection, we have seen that Smox–/– mice infected with H. pylori exhibit a significant reduction in gastric intramucosal carcinoma and extent of dysplasia. Spermine catabolism by SMOX generates 3-aminopropanol, which can spontaneously form acrolein, a reactive electrophilic aldehyde that has the potential to damage DNA and proteins. Our preliminary findings demonstrate that acrolein is produced in gastric tissues of H. pylori-infected FVB/N INS-GAS mice and is significantly reduced in Smox–/– FVB/N INS-GAS mice. Additionally, spermidine is an essential substrate for the synthesis of hypusine, a unique amino acid that is only found in the protein eukaryotic translation initiation factor 5A (EIF5A) by the action of the enzyme deoxyhypusine synthase (DHPS). Our recent work with human gastric organoids has revealed induction of hypusinated EIF5A levels with H. pylori infection, which was ablated with the chemical inhibitor of the pathway. Proteomic analysis on these organoids implicated hypusination as a critical pathway for oncogenesis. Taken together, we hypothesize that polyamine dysregulation due to SMOX activity in H. pylori-infected gastric epithelial cells leads to the generation of spermidine and acrolein, and upregulation of the hypusination pathway resulting in increased risk for gastric cancer development. Our specific aims are to determine: 1) the role of SMOX activity in gastric carcinogenesis, including effects of spermidine, spermine and acrolein in FVB/N INS-GAS mice. 2) if spermidine generated by SMOX contributes to gastric cancer development through hypusination using studies in human gastric organoids and mice with an epithelial-specific deletion of Dhps. This proposal seeks to elucidate the mechanisms by which SMOX induces gastric disease progression, thus identifying novel pathways to be targeted for therapeutic benefit, while providing the ideal training for my future career as a principal investigator.