FABP7 AND 6 AS A POTENTIAL TARGET AND MARKER IN CLEAR CELL RENAL CELL CARCINOMA

INTRODUCTION AND OBJECTIVES: Mef2A is a master transcription factor involved in cellular metabolism, epithelial-mesenchymal transition and invasion. Normally expressed at high levels in heart and skeletal muscle, it has recently been identified in leukemia, breast and hepatocellular carcinomas. As a tumor with significant metabolic derangement, we hypothesized that Mef2A is up-regulated in ccRCC, where it promotes tumor growth, migration and invasion. METHODS: Fluorescent immunohistochemistry was performed on normal kidney and RCC tissues collected from patients undergoing radical nephrectomy. A Mef2 dual luciferase reporter assay measured Mef2 transcriptional activity. Transient and long-term knockdown of Mef2A with siRNA and shRNA was induced in human RCC cells, which were then used in vitro and in a xenotransplant model of nude mice, respectively. Primeview Affymetrix gene chips and standard qRT-PCR identified and confirmed differentially expressed genes, respectively. A CCL20 ELISA measured concentration of CCL20 in RCC supernatant. Standard scratch and commercially available invasion assays were used. RESULTS: Patient RCC tissues express significantly higher levels of Mef2A compared to normal kidney tissues taken from the same patients, n1⁄452 (p 6 fold as well as the concentration of CCL20 in the supernatant of RCC cells (p<0.05). Knockdown of Mef2A reduced tumor cell migration and invasion (p<0.01, respectively). After one month, shMef2A tumor xenografts were significantly smaller compared to the shScr (scrambled shRNA) control tumors (p<0.01). CONCLUSIONS: Mef2A is up-regulated in human RCC compared to normal kidney from the same patients. Inhibition of Mef2A inhibits tumor cell migration and invasion as well as reduces tumor size, opening the potential of a new therapeutic target to advanced RCC, a tumor that remains fatal.