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）是最近发现的一种与FH基因的种系突变相关的遗传性肾癌，FH基因编码三羧酸（TCA）循环酶延胡索酸水合酶。HLRCC肾癌因其生物侵袭性而引人注目。不幸的是，对于晚期肾癌患者缺乏有效的全身治疗。受影响的人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，FH突变也已确定在一个子集的散发性子宫平滑肌瘤。HLRCC肿瘤形成可能是FH活性丧失的生化后果所致。特别地，转录因子缺氧诱导因子（HIF）的异常稳定（一种称为假缺氧的现象）可通过潜在致癌基因的上调导致肿瘤形成。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。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，在癌症生物学和肾脏氧化还原生理学专家的指导下，概述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医生-科学家，其目标是通过研究遗传形式的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，将确定FH丧失导致细胞ROS升高的基本机制。其次，活性氧对FH无效肿瘤中假性缺氧的贡献将通过检查ROS对该系统中HIF-11的翻译后修饰的影响来评估。第三，我们的研究结果的生物学意义将确定在原位肿瘤模型HLRCC。这些研究将通过结合基因置换和基因敲减的HLRCC细胞模型来实现。总体而言，该提案将利用HLRCC作为模型系统，以确定可能由ROS介导的HIF稳定化驱动的癌症患者的新治疗策略。 公共卫生相关性：肾癌在美国是一种越来越常见的恶性肿瘤。该提案旨在利用一种遗传性肾癌，称为遗传性平滑肌瘤病和肾细胞癌，以深入了解一般人群中更常见的肾癌变体。阐明这种特殊变体的分子途径可能有助于为癌症患者开发新的治疗策略。

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.