Investigating the role of PPAR gamma in clear cell renal cell carcinoma

研究 PPAR γ 在透明细胞肾细胞癌中的作用

• 批准号: 9320489
• 负责人: Danielle J. Sanchez
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320489
• 关键词: Binding; Biological Assay; Cardiac; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; ChIP-seq; Characteristics; Clear Cell; Clinical; Common Neoplasm; Data; Development; Disease; Dose; Esterification; Excision; Exhibits; Family member; Fatty Acids; Fibrinogen; Fractionation; Gene Expression; Gene Expression Profiling; Gene Targeting; Genetic Transcription; Genome; Goals; Growth; Histones; Hypoxia; Hypoxia Inducible Factor; Intracellular Transport; Kidney; Ligands; Lipids; Localized Disease; Luciferases; Malignant - descriptor; Measures; Mediating; Messenger RNA; Metabolic; Microarray Analysis; Modeling; Molecular; Molecular Chaperones; Mutation; Nuclear; Nuclear Receptors; Oncogenes; Operative Surgical Procedures; Organelles; PPAR alpha; PPAR gamma; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Play; Primary Neoplasm; Process; Proteins; Radiation therapy; Regulation; Renal Cell Carcinoma; Renal carcinoma; Reporter; Reporting; Resistance; Response Elements; Role; Solid Neoplasm; Survival Rate; Testing; Tissues; Transcriptional Activation; Tumor Suppressor Genes; United States; VHL Gene Inactivation; Western Blotting; base; chemotherapy; experimental study; fatty acid-binding proteins; knock-down; lipid biosynthesis; lipid metabolism; lipophilicity; long chain fatty acid; new therapeutic target; novel; outcome forecast; overexpression; promoter; public health relevance; radioresistant; response; small hairpin RNA; standard of care; targeted treatment; transcription factor; tumor; tumorigenesis; uptake

DESCRIPTION (provided by applicant): Clear cell renal cell carcinoma (ccRCC) is the most common and malignant subtype of kidney cancer, which carries a poor prognosis due to resistance to conventional chemotherapy and radiotherapy. Two molecular hallmarks of ccRCC are constitutive transcriptional activity of the hypoxia-inducible factor (HIF) proteins and storag of excess neutral lipid species in cytoplasmic lipid droplets. While recent studies have proposed that metabolic reprogramming of glycolytic and lipid anabolic processes are central to ccRCC tumorigenesis, factors imparting a lipogenic quality to these tumors remain incompletely characterized. The overall goal of this proposal is to elucidate mechanisms of regulation and functional roles of PPARγ in promoting ccRCC progression. Our preliminary data suggest that PPARγ, a master regulator of adipogenesis and lipid metabolism, is overexpressed in ccRCC tumors relative to normal kidney tissue and plays a critical role in maintaining viability of ccRCC cell lines. However, the mechanisms by which PPARγ promotes robust growth in ccRCC remain undefined. In Aim 1, I will test the hypothesis that HIF-1α mediates deregulated lipid metabolism in ccRCC through direct transcriptional activation of PPARγ. I will perform experiments to establish a HIF-1α-PPARγ axis, and characterize downstream changes in lipid metabolism that promote ccRCC progression. Moreover, I propose to identify a comprehensive set of PPARγ target genes in ccRCC through ChIP-seq and microarray experiments. In Aim 2, I will test the hypothesis that the lipid chaperone FABP6, which is associated with copy number amplification, mRNA overexpression, and nuclear localization in ccRCC tumors, enhances the activity of PPARγ. Previous reports suggest that fatty acid binding proteins (FABPs) can potentiate the activity of nuclear receptors including PPARγ, through delivery of activating ligands. Our preliminary experiments have demonstrated a significant block in proliferation in ccRCC cell lines following FABP6 suppression, yet the pathways FABP6 influence in ccRCC are not well understood. Together, these experiments will reveal how PPARγ is regulated and functions to maintain tumorigenesis in ccRCC. A better understanding of the factors which mediate altered lipid metabolism will lead to the development of novel, targeted therapies against this disease.

描述(申请人提供)：肾透明细胞癌(CcRCC)是肾癌中最常见和最恶性的亚型，由于对常规化疗和放射治疗耐药，预后较差。CcRCC的两个分子特征是低氧诱导因子(HIF)蛋白的结构性转录活性和细胞质脂滴中过量中性脂类的储存。虽然最近的研究表明糖酵解和脂质合成过程的代谢重编程是ccRCC肿瘤发生的核心，但赋予这些肿瘤造脂性质的因素仍然没有完全确定。这项建议的总体目标是阐明PPARγ在促进肾细胞癌进展中的调节机制和功能作用。我们的初步数据表明，与正常肾组织相比，PPARγ在肾细胞癌组织中过表达，并在维持肾细胞癌细胞系的活力方面发挥关键作用。然而，PPARγ促进CCRCC强劲增长的机制仍不清楚。在目标1中，我将验证这样的假设，即缺氧诱导因子-1α通过直接转录激活PPARγ介导肾小管细胞癌中去调节的脂代谢。我将进行实验，以建立HIF-1α-PPARγ轴，并表征促进肾细胞癌进展的脂质代谢的下游变化。此外，我还建议通过芯片序列和微阵列实验来鉴定肾细胞癌中一组完整的PPARγ靶基因。在目标2中，我将验证一种假设，即脂质伴侣FABP6在肾细胞癌中与拷贝数放大、基因过度表达和核定位相关，增强了PPARγ的活性。以往的报道表明，脂肪酸结合蛋白(FABP)可以通过传递激活配体来增强包括PPARγ在内的核受体的活性。我们的初步实验表明，FABP6抑制后ccRCC细胞系的增殖受到显著抑制，但FABP6对ccRCC的影响途径尚不清楚。总之，这些实验将揭示PPARγ是如何受到调控的，以及在CCRCC中维持肿瘤发生的功能。更好地了解介导脂代谢改变的因素将导致针对这种疾病的新的、有针对性的治疗方法的发展。