Role of SLC13A3 in Renal Cell Carcinoma

摘要 肾细胞癌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，RCC的发病率往往更高。由于缺乏诊断测试 而早期肾癌的无症状性质，约30%的患者患有晚期/转移性肾癌 最初的陈述。转移性肾癌是致命的，中位生存期不到2年。仍然有一个 迫切需要发现肾癌的分子驱动因素和与种族差异有关的生物标记物 并预测肾癌患者的临床结局。正常肾和肾癌组织的微阵列分析显示 SLC13A3在肾癌组织中下调；在非裔美国人肾癌患者中更明显，当 与白人和西班牙裔患者相比。SLC13A3是Krebs循环中间体和 谷胱甘肽。细胞内谷胱甘肽水平的降低已被证明可以诱导活性氧的产生。 (ROS)促进癌细胞的致癌功能。SLC13A3在肾癌细胞系中的过表达 细胞生长和克隆形成能力下降。发现SLC13A3的表达受表观遗传调控 通过DNA甲基化。这一提议将检验SLC13A3下调是一个分子的假设。 肾癌生长和进展的决定因素。此外，SLC13A3的下调与种族有关 并且是肾癌患者临床结果(转移、治疗反应、生存)的预测因子。 SLC13A3的功能、相关机制和表型读数将通过表达来研究 SLC13A3在肾癌细胞中的表达及其在正常肾上皮细胞中的下调。SLC13A3的作用 在RCC异种移植模型中，肿瘤生长和转移的表达将被研究。SLC13A3 在正常肾脏和肾癌组织中的表达将与临床结果和种族差异相关。这个 拟议的研究将是对SLC13A3在任何疾病类型中的功能作用的第一次调查， 包括癌症。这项研究应该揭示发生的分子变化和表型后果 由于在RCC损失了SLC13A3。该研究可能导致SLC13A3作为功能生物标记物的建立 对于RCC和在疾病严重性方面观察到的种族差异。

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.