Role of SLC13A3 in Renal Cell Carcinoma

SLC13A3 在肾细胞癌中的作用

• 批准号: 9325290
• 负责人: Andre R Jordan
• 金额: $ 3.37万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325290
• 关键词: African American; Age; Anchorage-Independent Growth; Antioxidants; Azacitidine; Biological Markers; CRISPR/Cas technology; Cell Line; Cell Proliferation; Cells; Cessation of life; Citrates; Citric Acid Cycle; Clinical; CpG Islands; DNA Methylation; Data; Development; Diagnosis; Diagnostic tests; Disease; Down-Regulation; Epigenetic Process; Epithelial Cells; Equilibrium; Evaluation; FDA approved; Gender; Glutamine; Glutathione; Goals; Growth; HIF1A gene; HK2 gene; Hispanics; Histology; Hypoxia; Immunoblot Analysis; Immunohistochemistry; In Situ Nick-End Labeling; Incidence; Investigation; Kidney Neoplasms; Laboratories; Lead; Link; Liver; Logistic Regressions; Luciferases; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Metastatic Neoplasm to the Lung; Metastatic Renal Cell Cancer; Methylation; Microarray Analysis; Mitogen-Activated Protein Kinases; Modality; Modeling; Molecular; Nature; Neoplasm Metastasis; Normal Cell; Oncogenic; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phenotype; Prognostic Marker; Promoter Regions; Race; Reactive Oxygen Species; Renal Cell Carcinoma; Renal carcinoma; Role; Sample Size; Severity of illness; Signal Pathway; Signal Transduction; Specimen; Succinates; Superoxides; Testing; Tissues; Transcript; Transfection; Transgenic Organisms; Trichostatin A; Tumor Suppressor Proteins; Tumor Tissue; Tumor Volume; Tumor stage; Weight; Xenograft Model; alpha ketoglutarate; bisulfite sequencing; bone; cDNA Arrays; cancer cell; cancer type; cell growth; cell motility; cohort; density; follow-up; hazard; in vivo; kidney cell; kidney epithelial cell; male; novel; overexpression; predict clinical outcome; protein expression; racial disparity; subcutaneous; therapeutic target; treatment response; tumor; tumor growth; tumor progression

ABSTRACT Renal cell carcinoma (RCC) is the most common type of kidney cancer. African Americans and males tend to have higher rates of RCC when compared to Whites and Hispanics. Due to the lack of diagnostic tests and the asymptomatic nature of RCC in early stages, about 30% of patients have advanced/metastatic RCC at initial presentation. Metastatic RCC is fatal, with median survival of less than 2 years. There still remains a great need for the discovery of molecular drivers of RCC, and biomarkers that associate with racial disparity and predict clinical outcome in RCC patients. Microarray analysis of normal kidney and RCC tissues revealed that SLC13A3 is downregulated in RCC tissues; more significantly in African American RCC patients, when compared to White and Hispanic patients. SLC13A3 is a transporter of Krebs cycle intermediates and glutathione. Decreased intracellular glutathione levels have been shown to induce reactive oxygen species (ROS) that promote oncogenic functions in cancer cells. Overexpression of SLC13A3 in RCC cell lines decreased cell growth and clonogenic survival. SLC13A3 expression was found to be epigenetically regulated by DNA methylation. This proposal will test the hypothesis that SLC13A3 downregulation is a molecular determinant of RCC growth and progression. Furthermore, SLC13A3 downregulation correlates with racial disparity and is a predictor of clinical outcome (metastasis, treatment response, survival) in RCC patients. SLC13A3 functions, associated mechanisms, and phenotypic readouts will be investigated by expressing SLC13A3 in RCC cells and by its downregulation in normal kidney epithelial cells. The effect of SLC13A3 expression on tumor growth and metastasis will be investigated in RCC xenograft models. SLC13A3 expression in normal kidney and RCC tissues will be correlated with clinical outcome and racial disparity. The proposed study will be the first investigation into the functional role of SLC13A3 in any disease type, including cancer. The study should reveal the molecular changes and phenotypic consequences that occur due to SLC13A3 loss in RCC. The study may lead to the establishment of SLC13A3 as functional biomarker for RCC and for the racial disparity observed in terms of disease severity.

摘要 肾细胞癌（RCC）是最常见的肾癌类型。非裔美国人和男性 与白人和西班牙裔相比，他们的肾细胞癌发病率往往更高。由于缺乏诊断测试 和RCC在早期阶段的无症状性质，约30%的患者在晚期/转移性RCC， 初次介绍。转移性RCC是致命的，中位生存期不到2年。仍然存在 非常需要发现RCC的分子驱动因素，以及与种族差异相关的生物标志物 并预测肾细胞癌患者的临床结局。正常肾脏和RCC组织的微阵列分析显示， SLC 13 A3在RCC组织中下调;在非裔美国人RCC患者中更显著， 与白色和西班牙裔患者相比。SLC 13 A3是克雷布斯循环中间体的转运蛋白， 谷胱甘肽细胞内谷胱甘肽水平降低已被证明可诱导活性氧 (ROS)促进癌细胞的致癌功能。肾癌细胞系中SLC 13 A3的过表达 细胞生长和克隆存活率降低。SLC 13 A3的表达被发现是表观遗传学调节的。 DNA甲基化。该提议将检验SLC 13 A3下调是一种分子机制的假设。 RCC生长和进展的决定因素。此外，SLC 13 A3下调与种族相关。 差异，并且是RCC患者中临床结果（转移、治疗反应、存活）的预测因子。 SLC 13 A3功能、相关机制和表型读数将通过表达 SLC 13 A3在RCC细胞中的表达以及其在正常肾上皮细胞中的下调。SLC 13 A3的作用 将在RCC异种移植模型中研究表达对肿瘤生长和转移的影响。SLC13A3 在正常肾和RCC组织中的表达将与临床结果和种族差异相关。的 所提出的研究将是对SLC 13 A3在任何疾病类型中的功能作用的首次研究， 包括癌症这项研究应该揭示发生的分子变化和表型后果 这是由于RCC中SLC 13 A3的缺失。该研究可能导致SLC 13 A3作为功能性生物标志物的建立 对于RCC和在疾病严重程度方面观察到的种族差异。