Role of fumarate hydratase in renal hypoxia and tumorigenesis

描述（由申请人提供）：遗传性平滑肌瘤病和肾细胞癌（HLRCC）是最近发现的一种遗传性肾癌，与FH基因的种系突变有关，FH基因编码三羧酸（TCA）循环酶富马酸水合酶。HLRCC肾癌具有显著的生物侵袭性。不幸的是，对于晚期肾癌患者缺乏有效的全身治疗。受影响的个体也有患皮肤和子宫平滑肌瘤的风险。此外，对受HLRCC肌瘤影响的妇女的干预通常需要在早期进行手术干预。有趣的是，在散发性子宫平滑肌瘤中也发现了FH突变。HLRCC肿瘤的形成可能是由于FH活性丧失的生化后果。特别是，转录因子缺氧诱导因子（hypoxia inducible factor， HIF）的异常稳定，一种被称为假缺氧的现象，可能通过上调潜在致癌基因导致肿瘤形成。假性缺氧也与其他几种肿瘤的发病机制有关，包括最常见的肾癌变体。我们实验室的初步数据表明，FH活性的丧失与细胞活性氧（ROS）水平的升高有关。因此，我们假设ROS驱动HLRCC中的假性缺氧。为了验证这一假设，在癌症生物学和肾氧化还原生理学专家的指导下，制定了一项为期五年的指导研究计划。该计划将使候选人成为一名独立的内科科学家，其目标是通过研究遗传性肾癌来进一步了解肾细胞癌。长期目标是将这些发现转化为有效的临床治疗方法。首先，FH缺失导致细胞ROS升高的基本机制将被确定。其次，通过检测ROS对该系统中HIF-11翻译后修饰的影响，评估活性氧对FH无效肿瘤中假性缺氧的贡献。第三，我们的发现的生物学意义将在原位肝癌模型中确定。这些研究将通过结合基因替代和基因敲低的细胞模型来实现。总的来说，本提案将利用HLRCC作为模型系统，为可能由ros介导的HIF稳定驱动的癌症患者确定新的治疗策略。

DESCRIPTION (provided by applicant): Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently identified hereditary form of kidney cancer linked to germline mutations of the FH gene which encodes the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase. HLRCC kidney cancers are remarkable for their biologic aggressiveness. Unfortunately, effective systemic therapies are lacking for patients with advanced kidney cancer. Affected individuals are also at risk for leiomyomas of the skin and uterus. In addition, intervention for women affected by HLRCC fibroids often requires surgical intervention at an early age. Interestingly, FH mutations have also been identified in a subset of sporadic uterine leiomyomas. HLRCC tumor formation may result from the biochemical consequences of loss of FH activity. In particular, aberrant stabilization of the transcription factor hypoxia inducible factor (HIF), a phenomenon referred to as pseudohypoxia, may result in tumor formation via upregulation of potentially carcinogenic genes. Pseudohypoxia has also been implicated in the pathogenesis of several other tumors including the most common variant of kidney cancer. Preliminary data from our laboratory indicates that loss of FH activity is associated with heightened cellular levels of reactive oxygen species (ROS). As such, we hypothesize that ROS drives pseudohypoxia in HLRCC. In order to test this hypothesis, a five-year mentored research plan is outlined under the guidance of experts in cancer biology and renal redox physiology. This plan will enable the candidate to become an independent physician-scientist whose goal is to further understanding of renal cell carcinoma through the study of inherited forms of kidney cancer. The long term objective will be to translate these findings into effective clinical therapeutics. First, the basic mechanisms by which loss of FH leads to elevated cellular ROS will be determined. Secondly, the contribution of reactive oxygen species to pseudohypoxia in FH null tumors will be assessed by examining the effects of ROS on post-translational modifications of HIF-11 in this system. Third, the biologic significance of our findings will be determined in an orthotopic tumor model of HLRCC. These studies will be achieved through a combination of gene replacement and gene knockdown cellular models of HLRCC. Overall, this proposal will utilize HLRCC as model system to identify new therapeutic strategies for patients with cancers that may be driven by ROS-mediated HIF stabilization. PUBLIC HEALTH RELEVANCE: Kidney cancer is an increasingly common malignancy in the United States. This proposal aims to utilize a hereditary form of kidney cancer, referred to as Hereditary Leiomyomatosis and Renal Cell Cancer, to provide insight into more common variants of kidney cancer in the general population. Elucidation of the molecular pathways of this particular variant may help develop novel therapeutic strategies for individuals with cancer.