Optional Splicing Of T-Cell Intercellular Antigen-1 (Tia-1), A Rna-Binding Protein Regulates Vegf Expression In Colorectal Cancer

To determine the role of post‐transcriptional regulation of Vascular Endothelial Growth Factor (VEGF) in colorectal cancer we investigated the relationship between VEGF and the RNA binding protein TIA‐1. An endogenous splice variant of TIA‐1 was expressed in 66% of colon cancer samples and in cancer cells with high angiogenic VEGF xxx expression. This splice variant resulted in a truncated protein termed short TIA‐1 (sTIA‐1). Whereas full length TIA‐1 bound to the VEGF xxx isoform (RNA immunoprecipitation, MS2‐Maltose Binding Protein assay) there was no TIA‐1 binding in cells expressing sTIA‐1. siRNA knockdown of TIA‐1 resulted in higher expression of total VEGF. Using VEGF terminal exon luciferase reporter constructs, TIA‐1 reduced translation of the angiogenic (exon 8a) but not the anti‐angiogenic (exon 8b) isoforms. In summary, we show that over expression of the wild type TIA‐1 in adenocarcinoma cells expressing sTIA‐1 results in restoration of the anti‐angiogenic VEGF isoforms. This suggest that TIA‐1 can act as both a splicing and splice specific translational regulator of VEGF and alternative splicing of TIA‐1 could lead to enhanced angiogenesis in colorectal cancer. Supported by AICR.