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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.; D'Silva, Olivia; Betteridge, Kai B.; Williams, Ann C.; Kerr, David J.; Salmon, Andrew H. J.; Oltean, Sebastian; Midgley, Rachel S.; Ladomery, Michael; 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 Thumbnail


Authors

Maryam A. Hamdollah Zadeh

Elianna M. Amin

Coralie Hoareau-Aveilla

Enric Domingo

Kirsty E. Symonds

Xi Ye

Katherine J. Heesom

Olivia D'Silva

Kai B. Betteridge

Ann C. Williams

David J. Kerr

Andrew H. J. Salmon

Sebastian Oltean

Rachel S. Midgley

Steven J. Harper

Alexander H. R. Varey

David O. Bates



Abstract

© 2014 The Authors. 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-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.

Citation

Hamdollah Zadeh, M. A., Amin, E. M., Hoareau-Aveilla, C., Domingo, E., Symonds, K. E., Ye, X., …Bates, D. O. (2015). Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance. Molecular Oncology, 9(1), 167-178. https://doi.org/10.1016/j.molonc.2014.07.017

Journal Article Type Article
Acceptance Date Jul 24, 2014
Online Publication Date Aug 20, 2014
Publication Date Jan 1, 2015
Deposit Date Aug 7, 2015
Publicly Available Date Apr 18, 2016
Journal Molecular Oncology
Print ISSN 1574-7891
Electronic ISSN 1878-0261
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 9
Issue 1
Pages 167-178
DOI https://doi.org/10.1016/j.molonc.2014.07.017
Keywords VEGF, splicing, TIA-1, VEGF165b
Public URL https://uwe-repository.worktribe.com/output/840047
Publisher URL http://dx.doi.org/10.1016/j.molonc.2014.07.017

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