VHL tumor suppressor gene and the initiation of renal cell carcinoma

描述（由申请人提供）：目前美国每年约有39,000例新的肾癌病例，导致超过13,000例死亡。传统的放疗和化疗是无效的。由于缺乏早期症状，早期发现也很困难。40-50%的患者发展为转移性疾病，其5年生存率仅为~10%。这些严峻的统计数据表明，迫切需要更好地了解肾癌的生物学。肾癌的一个重要特征是它与肿瘤抑制基因von Hippel-Lindau （VHL）的病变密切相关。该基因是以家族性VHL疾病命名的。高达70%的生殖系VHL突变携带者发展为透明细胞型肾细胞癌（ccRCC）。此外，在散发性ccRCC中，70-90%的患者存在VHL功能丧失，包括体细胞突变和表观遗传缺陷。VHL的功能是其E3泛素连接酶活性，其靶向缺氧诱导因子（HIF-a）的α亚基。然而，VHL也具有多种与hif无关的功能。目前尚不清楚VHL功能复杂谱的丧失如何共同促进ccRCC的发生。小鼠VHL肿瘤模型的缺乏进一步加剧了这种不确定性。我们在过去资助期的研究已经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，使用一种新的条件敲除策略，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，导致转移性ccRCC。这个模型应该允许我们阐明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。提出了四个特定的目标来表征新的VHL癌症模型：确定VHL- hif轴在VHL基因敲除病变中的组织来源及作用。目标2。目的：阐明VHL突变细胞中EMT信号的分子和细胞机制。目标3。目的：探讨VHL突变肾脏炎症的发生机制。目标4。分析与VHL肿瘤进展相关的基因表达模式。

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.