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（由申请人提供）：透明细胞肾细胞癌（ccRCC）是肾癌中最常见和最恶性的亚型，由于对常规化疗和放疗的耐药性，其预后较差。ccRCC的两个分子标志是缺氧诱导因子（HIF）蛋白的组成性转录活性和细胞质脂滴中过量中性脂质种类的储存。虽然最近的研究提出糖酵解和脂质合成代谢过程的代谢重编程是ccRCC肿瘤发生的核心，但赋予这些肿瘤脂肪生成质量的因素仍不完全表征。该提案的总体目标是阐明PPARγ在促进ccRCC进展中的调节机制和功能作用。我们的初步数据表明，相对于正常肾组织，脂肪生成和脂质代谢的主要调节因子PPARγ在ccRCC肿瘤中过表达，并在维持ccRCC细胞系的活力方面发挥关键作用。然而，PPARγ促进ccRCC稳健生长的机制仍不清楚。在目的1中，我将检验HIF-1α通过直接转录激活PPARγ介导ccRCC中脂质代谢失调的假设。我将进行实验以建立HIF-1α-PPARγ轴，并表征促进ccRCC进展的脂质代谢的下游变化。此外，我建议通过ChIP-seq和微阵列实验来识别ccRCC中的一组全面的PPARγ靶基因。在目标2中，我将检验这样的假设，即与ccRCC肿瘤中拷贝数扩增、mRNA过表达和核定位相关的脂质伴侣FABP 6增强了PPARγ的活性。脂肪酸结合蛋白（fatty acid binding proteins，FABPs）可通过传递活化配体增强核受体（包括PPARγ）的活性。我们的初步实验已经证明，在FABP 6抑制后，ccRCC细胞系中的增殖被显著阻断，但FABP 6在ccRCC中的影响途径尚未得到很好的理解。总之，这些实验将揭示PPARγ是如何调节和发挥作用以维持ccRCC中的肿瘤发生的。更好地了解介导脂质代谢改变的因素将导致针对这种疾病的新型靶向治疗的发展。