Role of SLC13A3 in Renal Cell Carcinoma

摘要

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.