Abstract A4: CXCR3-B-mediated signaling suppresses c-MET-mediated angiogenic signals through the down-regulation of HO-1 and VEGF expression

Abstract Chemokine receptor CXCR3 gene encodes two splice variants with opposite functions; CXCR3-A promotes cell growth whereas CXCR3-B is growth inhibitory. Down-regulation of CXCR3-B promotes survival of many cancer cell types including Renal Cell Carcinoma (RCC) cells. However, the molecular signaling events that mediate down-regulation of CXCR3-B are not fully understood. Growth factors mediated signaling events govern Alternative Splicing (AS) of genes. The receptor tyrosine kinase c-MET is over-expressed in RCC cells and signaling through its ligand Hepatocyte Growth Factor (HGF) can play a major role in the growth and survival of tumor. In this study, we investigated the role of c-MET-mediated signaling in the modulation of AS of CXCR3 gene and analyzed the impact of CXCR3-B-mediated growth inhibitory signals on c-MET-mediated angiogenic pathway in RCC cells. We found that HGF treatment down-regulated CXCR3-B expression in both primary renal epithelial (RPTEC) and RCC (786-O and ACHN) cells. We found that c-MET-mediated signaling increased the expression of gene AS regulating protein SAM68 (also a prognostic marker for RCC) and modulated the association of SAM68 with CXCR3 gene. Utilizing gene over expression approach, we found that CXCR3-B-mediated signaling down-regulated the expression of cytoprotective molecule Hemeoxygenease-1 (HO-1) and angiogenic factor VEGF at both transcription and protein levels. We also found that CXCR3-B-mediated signaling down-regulated c-MET-induced secretion of angiogenic factors from RCC cells, as observed by the decrease in the tube formation ability of endothelial (HUVEC) cells grown with supernatant obtained from CXCR3-B over-expressing RCC cells culture. Together, we suggest that CXCR3-B-mediated signaling acts as a checkpoint for c-MET-mediated angiogenic signals in RCC. We propose a novel function for c-MET-mediated signaling in promoting angiogenesis in renal cancer cells through the down-regulation of CXCR3-B expression. Citation Format: Murugabaskar Balan, Soumitro Pal. CXCR3-B-mediated signaling suppresses c-MET-mediated angiogenic signals through the down-regulation of HO-1 and VEGF expression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A4.