The impact of KRAS mutations on VEGF-A production and tumour vascular network
Author
Figueras, Agnès
Arbós Vilà, Maria Antonia
Quiles Pérez, María Teresa
Viñals, Francesc
Germà, Josep Ramón
Capellà, Gabriel
Publication date
2013-03-18ISSN
1471-2407
Abstract
Background: The malignant potential of tumour cells may be influenced by the molecular nature of KRAS mutations being codon 13 mutations less aggressive than codon 12 ones. Their metabolic profile is also different, with an increased anaerobic glycolytic metabolism in cells harbouring codon 12 KRAS mutations compared with cells containing codon 13 mutations. We hypothesized that this distinct metabolic behaviour could be associated with different HIF-1α expression and a distinct angiogenic profile. Methods: Codon13 KRAS mutation (ASP13) or codon12 KRAS mutation (CYS12) NIH3T3 transfectants were analyzed in vitro and in vivo. Expression of HIF-1α, and VEGF-A was studied at RNA and protein levels. Regulation of VEGF-A promoter activity was assessed by means of luciferase assays using different plasmid constructs. Vascular network was assessed in tumors growing after subcutaneous inoculation. Non parametric statistics were used for analysis of results. Results: Our results show that in normoxic conditions ASP13 transfectants exhibited less HIF-1α protein levels and activity than CYS12. In contrast, codon 13 transfectants exhibited higher VEGF-A mRNA and protein levels and enhanced VEGF-A promoter activity. These differences were due to a differential activation of Sp1/AP2 transcription elements of the VEGF-A promoter associated with increased ERKs signalling in ASP13 transfectants. Subcutaneous CYS12 tumours expressed less VEGF-A and showed a higher microvessel density (MVD) than ASP13 tumours. In contrast, prominent vessels were only observed in the latter. Conclusion: Subtle changes in the molecular nature of KRAS oncogene activating mutations occurring in tumour cells have a major impact on the vascular strategy devised providing with new insights on the role of KRAS mutations on angiogenesis.
Document Type
Article
Document version
Accepted version
Language
English
Subject (CDU)
61 - Medical sciences
Keywords
Mutació (Biologia)
Angiogènesi
Tumors
Càncer
Mutación (Biología)
Angiogénesis
Tumores
Cáncer
Mutations
Tumours
Angiogenesis
Cancer
Pages
11
Publisher
Springer Nature
Collection
13;
Is part of
BMC Cancer
Citation
Figueras, Agnès; Arbos, Maria Antonia; Quiles, Maria Teresa [et al.]. The impact of KRAS mutations on VEGF-A production and tumour vascular network. BMC Cancer, 2013, vol. 13, p. 1-11. Disponible en: <https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-13-125#Ack1>. Fecha de acceso: 27 dic. 2019. DOI: 10.1186/1471-2407-13-125
Grant agreement number
info:eu-repo/grantAgreement/ES/1PE/SAF2012-3363
info:eu-repo/grantAgreement/ES/3PN/SAF2010-20859
info:eu-repo/grantAgreement/ES/3PN/SAF2009–07319
This item appears in the following Collection(s)
- Ciències de la Salut [738]
Rights
© 2013 Figueras et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/2.0