Intercepting novel functions of AURKA in gastric tumorigenesis

拦截 AURKA 在胃肿瘤发生中的新功能

• 批准号: 10515693
• 负责人: WAEL EL-RIFAI
• 金额: $ 44.43万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515693
• 关键词: 20q; Biological; Biological Factors; Biology; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Catchment Area; Cells; Cellular Stress; Cessation of life; Chemoresistance; Chronic; Clinical; Clinical Trials; Comprehensive Cancer Center; Diagnosis; Diagnostic; Environment; Epithelial Cells; Etiology; Eukaryotic Initiation Factor-4E; Florida; Genes; Genetically Engineered Mouse; Helicobacter Infections; Helicobacter pylori; Human; In Vitro; Incidence; Infection; Intercept; LGR5 gene; Mediating; Molecular; Oncogenic; Oncology; Organoids; Pathology; Population; Property; Proteins; Resistance; Rest; Risk Factors; Role; Sampling Studies; Signal Transduction; South America; Southeastern Asia; Stomach Carcinoma; Survival Rate; Technology; Testing; Therapeutic; Tissues; Translational Activation; Translations; Treatment Efficacy; United States; Universities; Work; aurora kinase A; base; carcinogenicity; chemotherapy; clinically relevant; docetaxel; evidence base; experience; fitness; functional outcomes; gastric carcinogenesis; gastric tumorigenesis; gastroesophageal cancer; human tissue; in vitro Model; in vivo; in vivo Model; malignant stomach neoplasm; mouse model; novel; overexpression; patient derived xenograft model; preclinical study; prognostic; protein expression; response; stem; therapy resistant; translational study; treatment response; tumorigenesis; tumorigenic

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.

摘要/总结 胃癌（GAC）是世界范围内癌症相关死亡的第三大常见原因， 每年有超过70万人死亡不幸的是，大多数胃癌患者在晚期被诊断出来。 在美国为III期或IV期，对治疗反应差，5年生存率为5.2%。 幽门螺杆菌（Helicobacter pylori，H. pylori），一种I型致癌物，是胃溃疡的主要危险因素。 致癌作用螺杆菌感染幽门创造了一个独特的环境，上皮细胞必须适应 慢性细胞应激和被迫发展适应性生存健身属性，不仅促进 肿瘤发生以及对化疗药物的抗性。了解分子功能 致癌生物因子如H.幽门螺杆菌感染是发展循证医学的关键步骤 基于胃癌发生的生物学和分子基础的治疗方法。 我们已经发现极光激酶A（AURKA）是20 q扩增子处的关键靶点，在细胞中过表达。 大约60%的胃癌。我们发现了AURKA在促进EIF 4 E和cap-方面的新功能 依赖翻译的关键基因，如SOX 9和LGR 5，促进生存和扩大的 致瘤细胞对感染的反应。我们还发现，耐药细胞富含 AURKA、SOX 9和LGR 5水平较高。这项建议有三个具体目标，包括机械， 使用独特的体外和体内模型进行功能和翻译研究，包括类器官培养和 小鼠模型。在目的1中，我们将研究AURKA在重编程翻译的 机械响应感染H.幽门。我们将确定AURKA依赖函数， 促进胃肿瘤发生和对治疗的抗性，使用目的2中的体内模型。平移 我们的发现的意义和靶向AURKA的治疗效果将在目标3中进行研究。后 完成这项工作后，我们预计将揭开AURKA和EIF 4 E之间串扰的新范式- 依赖的翻译机制在促进胃肿瘤发生和对治疗的抵抗中的作用。