VHL tumor suppressor gene and the initiation of renal cell carcinoma

VHL抑癌基因与肾细胞癌的发生

基本信息

批准号：
8494112
负责人：
TIEN HSU
金额：
$ 7.55万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494112
关键词：
Accounting Adaptor Signaling Protein Adult Biological Assay Cancer Biology Cancer Model Cell Culture Techniques Cells Cessation of life Characteristics Clear Cell Complex Conditioned Culture Media Defect Development Disease Disseminated Malignant Neoplasm Drosophila genus Early Diagnosis Epigenetic Process Erythropoietin Event Excision Familial Polycythemia Fibrosis Funding Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Epistasis Genetic Markers Genetic Models Germ Lines Glucose Glycolysis Human Hypoxia Inducible Factor In Vitro Incidence Inflammation Injury Kidney Knock-out Knockout Mice Lasers Lesion Loss of Heterozygosity Malignant Epithelial Cell Malignant Neoplasms Metabolic Metabolic Pathway Metastatic to Modeling Molecular Molecular Profiling Mus Mutation Names Operative Surgical Procedures Pathway interactions Patients Premalignant Preventive Primary Lesion Process Procollagen-Proline Dioxygenase Proteins Radiation Relapse Renal Cell Carcinoma Renal carcinoma Renal tubule structure Reporter Genes Role Signal Transduction Somatic Mutation Survival Rate Symptoms System Therapeutic Time Tissues Tumor Suppressor Genes Uncertainty United States VHL gene VHL mutation Vascular Endothelial Growth Factors Von Hippel-Lindau Syndrome attributable mortality cancer cell cancer type cell type chemokine cytokine design epithelial to mesenchymal transition expectation in vivo kidney cell mouse model mutant mutant mouse model novel protein degradation public health relevance statistics tumor tumor initiation tumor progression tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): There are presently about 39,000 new cases of renal cancer in the United States each year, resulting in over 13,000 deaths. Traditional radiation and chemo-therapies are ineffective. Early detection is also difficult because of a lack of early symptoms. 40-50% of patients develop metastatic disease, for whom the 5-year survival rate is only ~10%. Such grim statistics point to an urgent need for better understanding of the kidney cancer biology. One important characteristic of kidney cancer is its strong association with lesions in one gene, the von Hippel-Lindau (VHL) tumor suppressor gene. The gene is named after the familial VHL disease. Up to 70% of the carriers of germ line VHL mutations develop renal cell carcinoma of the clear-cell type (ccRCC). In addition, loss of VHL function, including somatic mutations and epigenetic defects, is found in 70-90% of sporadic ccRCC. The best-documented function of VHL is its E3 ubiquitin ligase activity that targets the alpha subunit of the hypoxia-inducible factor (HIF-a). However, VHL also possess multiple HIF-independent functions. It is not known how loss of the complex spectrum of VHL functions collectively contribute to the initiation of ccRCC. The uncertainties are further compounded by a lack of VHL cancer model in mouse. Our studies in the past funding period have elucidated a novel epithelial-to-mesenchymal transition (EMT) pathway that has been implicated in kidney injury and fibrosis. Most importantly, using a new conditional knockout strategy, we have, for the first time, developed a genuine mouse ccRCC model that recapitulates features of kidney inflammation and fibrosis, leading to metastatic ccRCC. This model should allow us to elucidate the earliest event in ccRCC and point to potential preventive and curative strategies for this deadly disease. Four Specific Aims are proposed to characterize the new VHL cancer model: Aim 1. To determine the tissue origin and the role of VHL-HIF axis in VHL knockout lesions. Aim 2. To elucidate the molecular and cellular mechanisms of EMT signaling in VHL mutant cells. Aim 3. To elucidate the mechanism of inflammation in VHL mutant kidney. Aim 4. To profile the gene expression pattern associated with VHL tumor progression. PUBLIC HEALTH RELEVANCE: Mutations in VHL tumor suppressor gene are the cause of a majority of kidney cancers, but the exact tumorigenic mechanism of this deadly disease is still unknown. We recently developed a VHL mutant mouse model that for the first time, generated kidney cancer and suggested an intriguing possibility of inflammation prior to tumor development. Our proposed study should shed lights on the process of kidney cancer formation and point to preventive and curative strategies.

描述（由申请人提供）：美国目前每年大约有39,000例新的肾癌病例，导致13,000多人死亡。传统的辐射和化学治疗无效。由于缺乏早期症状，早期发现也很困难。 40-50％的患者患有转移性疾病，对他们的5年生存率仅约10％。这种严峻的统计数据表明，迫切需要更好地了解肾癌生物学。肾癌的一个重要特征是它与一个基因中的病变的牢固关联，即von Hippel-Lindau（VHL）肿瘤抑制基因。该基因以家族性VHL疾病的名字命名。多达70％的生殖系VHL突变携带者会出现透明细胞类型（CCRCC）的肾细胞癌。此外，在70-90％的散发性CCRCC中发现了VHL功能的丧失，包括体细胞突变和表观遗传缺陷。 VHL最有记录的功能是其E3泛素连接酶活性，其靶向缺氧诱导因子的α亚基（HIF-A）。但是，VHL还具有多个与HIF无关的函数。尚不清楚VHL功能的复杂频谱的损失如何共同促进CCRCC的启动。在小鼠中缺乏VHL癌模型，不确定性进一步加剧了。过去的资金期间，我们的研究阐明了与肾脏损伤和纤维化有关的新型上皮到间质转变（EMT）途径。最重要的是，使用新的条件敲除策略，我们首次开发了一种真正的小鼠CCRCC模型，该模型概括了肾脏炎症和纤维化的特征，从而导致转移性CCRCC。该模型应该使我们能够阐明CCRCC中最早的事件，并指出这种致命疾病的潜在预防和治愈策略。提出了四个具体目标来表征新的VHL癌症模型：目标1。确定组织起源和VHL-HIF轴在VHL敲除病变中的作用。目标2。阐明VHL突变细胞中EMT信号的分子和细胞机制。目的3。阐明VHL突变肾中炎症机制。目标4。介绍与VHL肿瘤进展相关的基因表达模式。公共卫生相关性：VHL肿瘤抑制基因的突变是大多数肾脏癌的原因，但是这种致命疾病的确切肿瘤机制仍然未知。我们最近开发了一种VHL突变小鼠模型，该模型首次引起了肾癌，并提出了在肿瘤发育之前引起炎症的有趣可能性。我们提出的研究应阐明肾癌形成的过程以及预防和治愈策略的点。