Intercepting novel functions of AURKA in gastric tumorigenesis

摘要/摘要 胃癌(GAC)是世界上与癌症相关的死亡的第三大常见原因，导致的 每年有超过70万人死亡。不幸的是，大多数胃癌患者的确诊时间较晚。 美国的晚期(III期或IV期)，治疗反应差，五年存活率为5.2%。 感染幽门螺杆菌是胃病的主要危险因素，幽门螺杆菌是一种I型致癌物质。 致癌。幽门螺杆菌感染创造了上皮细胞必须适应的独特环境 慢性细胞应激并被迫发展出适应性生存适应特性，不仅促进 肿瘤的发生也会对化疗药物产生耐药性。对分子功能的理解 幽门螺杆菌感染等致癌生物因素是开展循证研究的关键一步 以胃癌发生的生物学和分子基础为基础的治疗方法。 我们发现极光蛋白A(Aurora kinaseA，AURKA)是20Q扩增子的关键靶点，在 大约60%的胃癌。我们发现了AURKA在促进eIF4E和CAP-2中的新功能。 SOX9和LGR5等促进肿瘤存活和扩张的关键基因的依赖翻译 对感染作出反应的致瘤细胞。我们还发现，耐药细胞被浓缩为 高水平的AURKA、SOX9和LGR5。这项提议有三个具体目标，包括机械化， 使用独特的体外和体内模型进行的功能和翻译研究，包括有机培养和 老鼠模型。在目标1中，我们将研究AURKA在重新编程翻译过程中的机械作用 应对幽门螺杆菌感染的机器。我们将在中确定AURKA依赖函数 利用AIM体内模型促进胃肿瘤的发生和耐药2.翻译的 我们的发现的意义和以AURKA为靶点的治疗效果将在目标3中进行调查。 完成这项工作后，我们预计将揭开AURKA和eIF4E之间的串扰的新范式- 依赖的翻译机制促进胃肿瘤的发生和对治疗的抵抗。

ABSTRACT/SUMMARY Gastric carcinoma (GAC) is the third most common cause of cancer-related death world-wide, causing more than 700,000 deaths each year. Unfortunately, the majority of gastric cancer patients are diagnosed at a late stage (Stage III or IV) in the United States, with a poor response to therapy and five-year survival rate of 5.2%. Infection with Helicobacter pylori (H. pylori), a type I carcinogen, is the main risk factor for gastric carcinogenesis. Infection with H. pylori creates a unique environment where epithelial cells must adapt to chronic cellular stress and are forced develop adaptive survival fitness properties that not only promote tumorigenesis but also resistance to chemotherapeutics. Understanding the molecular functions of carcinogenic biological factors such as H. pylori infection is a key step for developing evidence-based therapeutic approaches that are founded on the biology and molecular underpinning of gastric carcinogenesis. We have found that Aurora kinase A (AURKA) is a critical target at the 20q amplicon, overexpressed in approximately 60% of gastric cancers. We identified novel functions of AURKA in promoting EIF4E and cap- dependent translation of critical genes such as SOX9 and LGR5 that promote survival and expansion of tumorigenic cells in response to infection. We have also found that treatment-resistant cells were enriched for high levels of AURKA, SOX9, and LGR5. This proposal has three specific aims that include mechanistic, functional, and translational studies using unique in vitro and in vivo models, including organoid cultures and mouse models. In aim 1, we will investigate the mechanistic role of AURKA in reprogramming the translational machinery in response to infection with H. pylori. We will determine the AURKA-dependent functions in promoting gastric tumorigenesis and resistance to therapy, using in vivo models in Aim 2. The translational significance of our findings and therapeutic efficacy of targeting AURKA will be investigated in Aim 3. Upon completion of this work, we expect to unveil a new paradigm of cross-talk between AURKA and EIF4E- dependent translational machinery in promoting gastric tumorigenesis and resistance to therapy.