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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：
8828100
负责人：
TIEN HSU
金额：
$ 32.85万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828100
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 Health 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 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.

描述（由申请人提供）：目前美国每年约有 39,000 例新发肾癌病例，导致 13,000 多人死亡。传统的放射疗法和化学疗法无效。由于缺乏早期症状，早期发现也很困难。 40-50%的患者出现转移性疾病，其5年生存率仅为10%左右。如此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种基因——von Hippel-Lindau (VHL) 抑癌基因——的病变密切相关。该基因以家族性 VHL 疾病命名。高达 70% 的种系 VHL 突变携带者会发展为透明细胞型肾细胞癌 (ccRCC)。此外，70-90% 的散发性 ccRCC 存在 VHL 功能丧失，包括体细胞突变和表观遗传缺陷。 VHL 的最佳记录功能是其针对缺氧诱导因子 (HIF-a) 的 α 亚基的 E3 泛素连接酶活性。然而，VHL 还拥有多种与 HIF 无关的功能。目前尚不清楚 VHL 复杂功能谱的丧失如何共同导致 ccRCC 的发生。由于缺乏小鼠 VHL 癌症模型，进一步加剧了不确定性。我们在过去的资助期间的研究阐明了一种新的上皮间质转化（EMT）途径，该途径与肾损伤和纤维化有关。最重要的是，利用新的条件敲除策略，我们首次开发了真正的小鼠 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 的最早事件，并指出这种致命疾病的潜在预防和治疗策略。提出了四个具体目标来表征新的 VHL 癌症模型：目标 1. 确定组织起源以及 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 信号转导的分子和细胞机制。目的3.阐明VHL突变肾脏的炎症机制。目标 4. 分析与 VHL 肿瘤进展相关的基因表达模式。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis.

DOI：
10.1128/mcb.01578-09
发表时间：
2010-08
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Hsouna A;Nallamothu G;Kose N;Guinea M;Dammai V;Hsu T
通讯作者：
Hsu T

Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms.

DOI：
10.1038/onc.2011.442
发表时间：
2012-05-03
期刊：
ONCOGENE
影响因子：
8
作者：
Hsu, T.
通讯作者：
Hsu, T.

Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model.

粒细胞中肿瘤抑制基因 von Hippel-Lindau (VHL) 的失活有助于小鼠模型中肝血管瘤的发展。

DOI：
10.1186/s12885-016-2802-3
发表时间：
2016
期刊：
BMC cancer
影响因子：
3.8
作者：
Bader,HannahL;Hsu,Tien
通讯作者：
Hsu,Tien

Systemic VHL gene functions and the VHL disease.

DOI：
10.1016/j.febslet.2012.04.032
发表时间：
2012-06-04
期刊：
FEBS letters
影响因子：
3.5
作者：
Bader HL;Hsu T
通讯作者：
Hsu T

Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23.

DOI：
10.1186/1741-7007-12-12
发表时间：
2014-02-14
期刊：
BMC biology
影响因子：
5.4
作者：
Ignesti M;Barraco M;Nallamothu G;Woolworth JA;Duchi S;Gargiulo G;Cavaliere V;Hsu T
通讯作者：
Hsu T