Renal Cell Carcinoma (RCC): NEDD9, Aurora kinase A (AURKA), and their interrelation with von Hippel-Lindau gene (VHL) in tumor pathology

肾细胞癌 (RCC)：NEDD9、极光激酶 A (AURKA) 及其与肿瘤病理学中 von Hippel-Lindau 基因 (VHL) 的相互关系

• 批准号: 259273335
• 负责人: Dr. Tamina Seeger-Nukpezah
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/259273335?language=en
• 关键词: Renal; Cell; Carcinoma; RCC; NEDD9

Kidney cancer is one of the top 10 most common cancers for both woman and men, with renal cell carcinoma (RCC) responsible for over 80% of the cases. Clear cell RCC (ccRCC) represents the most common subgroup of RCC (75% of cases) and is strongly associated with genetic lesions in the von Hippel-Lindau (VHL) gene, leading to upregulation of HIF1- and 2-alpha, major players in the pathogenesis of RCC. Recently, the oncogenes AURKA and NEDD9 (also: enhancer of filamentation 1 (HEF1) or CAS-L) were found to be upregulated by HIF-alpha upon loss of VHL in RCC cells, promoting cell migration, invasion and cilia disassembly. Moreover AURKA is interacting with and phosphorylating VHL, leading to tumor progression in preclinical RCC studies. Our preliminary data show that also NEDD9 associates with VHL and that NEDD9 overexpression in RCC samples significantly associates with patient survival.To test whether NEDD9 and AURKA drive RCC progression and which mechanisms are involved, we will first characterize the interaction between NEDD9 and VHL. Then we will employ two different transgenic mouse models and two different models utilizing human RCC cells: a xenograft model and a RCC tumor microenvironment-mimicking 3D in vitro model. These models will allow us to directly test the role of NEDD9 and its signaling partner AURKA in tumor progression and in cellular processes relevant for RCC pathogenesis in conditions with and without VHL deficiency.The ultimate goal in this work is to better understand the pathogenesis of RCC tumor initiation and progression allowing the development of novel, tailored treatment strategies based on the interplay of NEDD9, AURKA and VHL in RCC.

肾癌是女性和男性最常见的十大癌症之一，其中肾细胞癌（RCC）占80%以上的病例。透明细胞肾细胞癌（ccRCC）代表最常见的RCC亚组（75%的病例），与von Hippel-Lindau（VHL）基因的遗传病变密切相关，导致HIF 1-和2-α上调，这是RCC发病机制的主要参与者。最近，发现癌基因AURKA和NEDD9（也称为：表达增强子1（HEF1）或CAS-L）在RCC细胞中VHL丧失后被HIF-α上调，促进细胞迁移、侵袭和纤毛分解。此外，AURKA与VHL相互作用并磷酸化VHL，导致临床前RCC研究中的肿瘤进展。我们的初步数据表明，也NEDD9与VHL和NEDD9在RCC样品中的过表达显着与患者的survival.To测试是否NEDD9和AURKA驱动RCC的进展和哪些机制参与，我们将首先表征NEDD9和VHL之间的相互作用。然后，我们将采用两种不同的转基因小鼠模型和两种不同的利用人RCC细胞的模型：异种移植模型和RCC肿瘤微环境模拟3D体外模型。这些模型将使我们能够直接测试NEDD9及其信号伙伴AURKA在肿瘤进展中的作用，以及在VHL缺乏和不缺乏的条件下与RCC发病机制相关的细胞过程中的作用，这项工作的最终目标是更好地了解RCC肿瘤发生和进展的发病机制，从而基于NEDD9，AURKA和VHL在RCC中的相互作用开发新的，定制的治疗策略。