Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance

作者：Zadeh Maryarn A Hamdollah; Amin Elianna M; Hoareau Aveilla Coralie; Domingo Enric; Symonds Kirsty E; Ye Xi; Heesom Katherine J; Salmon Andrew; D'Silva Olivia; Betteridge Kai B; Williams Ann C; Kerr David J; Salmon Andrew H J; Oltean Sebastian; Midgley Rachel S; Ladomery Michael R; Harper Steven J; Varey Alexander H R; Bates David O^*

来源：Molecular Oncology, 2015, 9(1): 167-178.

DOI：10.1016/j.molonc.2014.07.017

• VEGF
• Splicing
• TIA-1
• VEGF(165)b

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 overexpression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A(165)b. Whereas flTIA-1 selectively bound VEGF-A(165) mRNA and increased translation of VEGF-A(165)b, 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. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

• 出版日期2015-1