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Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286123/ https://www.ncbi.nlm.nih.gov/pubmed/25224594 http://dx.doi.org/10.1016/j.molonc.2014.07.017 |
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author | Hamdollah Zadeh, Maryam A. 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. |
author_facet | Hamdollah Zadeh, Maryam A. 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. |
author_sort | Hamdollah Zadeh, Maryam A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4286123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-42861232015-01-13 Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance Hamdollah Zadeh, Maryam A. 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. Mol Oncol Research Articles 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. John Wiley and Sons Inc. 2014-08-20 2015-01 /pmc/articles/PMC4286123/ /pubmed/25224594 http://dx.doi.org/10.1016/j.molonc.2014.07.017 Text en © 2015 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/3.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Hamdollah Zadeh, Maryam A. 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. Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title | Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title_full | Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title_fullStr | Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title_full_unstemmed | Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title_short | Alternative splicing of TIA‐1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
title_sort | alternative splicing of tia‐1 in human colon cancer regulates vegf isoform expression, angiogenesis, tumour growth and bevacizumab resistance |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286123/ https://www.ncbi.nlm.nih.gov/pubmed/25224594 http://dx.doi.org/10.1016/j.molonc.2014.07.017 |
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