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The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A165b. Whereas flTIA-1 selectively bound VEGF-A165 mRNA and increased translation of VEGF-A165b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy.

Original publication

DOI

10.1016/j.molonc.2014.07.017

Type

Journal article

Journal

Mol Oncol

Publication Date

01/2015

Volume

9

Pages

167 - 178

Keywords

Splicing, TIA-1, VEGF, VEGF(165)b, Alternative Splicing, Animals, Bevacizumab, Colonic Neoplasms, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Heterografts, Humans, Mice, Nude, Neoplasm Proteins, Neoplasm Transplantation, Neovascularization, Pathologic, Poly(A)-Binding Proteins, Protein Isoforms, Vascular Endothelial Growth Factor A