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DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

Oncogene volume 30, pages 668–678 (2011)Cite this article

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Abstract

DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell–cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

BMP2:

bone morphogenetic protein 2

CDDP:

Cisplatin

MERTK:

c-mer proto-oncogene tyrosine kinase

PTPRK:

protein tyrosine phosphatase receptor type K

VEGFC and D:

vascular endothelial growth factor C and D

VEGFR3:

vascular endothelial growth factor receptor3

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Acknowledgements

Ibanez de Caceres was partially supported by the Fondo de Investigacion Sanitaria (ISCIII) through the ‘Miguel Servet’ program (CP 08/000689); VM-A is a recipient of FIS fellowship. IS-P is in receipt of career development awards from the Ramón y Cajal program funded by the Spanish Ministerio de Educación y Ciencia. We acknowledge Leandro Sastre for helping with cTAP constructs and helpful discussions. We thank Silvia Menéndez (Hospital del Mar-IMAS) and Nuria Pérez-González (Fundación Jiménez Díaz) for the technical support. We also thank Javier Perez and Fernando Núñez (IIB) for the artwork and animal facility, respectively. This work was supported by PI05/2019, PI05/1305, PI06/1513, PI081485, PI09/1296, PS09/01285 and PS09/00472 (Spanish Health Ministry grant ‘Fondo de Investigación Sanitaria’), SAF2007-62292 (Ministerio de Educación y Ciencia grant), SAL-0311-2006 (Comunidad Autónoma de Madrid) and RTICC 06/0020/19 grant. We especially thank Fundació Privada Cellex (Barcelona) and Fundación Médica Mutua Madrileña for a generous grant to the Medical Oncology Service, Hospital del Mar-IMAS and to Instituto de Investigaciones Biomédicas (IIB), respectively.

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Author notes

  1. V Moncho-Amor and I Ibañez de Cáceres: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Investigaciones Biomedicas C.S.I.C./U.A.M, CIBER de Enfermedades Raras (CIBERER), IdiPAZ, Madrid, Spain

    V Moncho-Amor, I Sánchez-Pérez & R Perona

  2. Research Unit, Oncology Research Laboratory, FIB-La Paz University Hospital, IdiPAZ, Madrid, Spain

    I Ibañez de Cáceres

  3. Division of Oncology, Laboratory of Pharmacogenomics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain

    E Bandres & J García-Foncillas

  4. Department Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biomédicas C.S.I.C./U.A.M, Madrid, Spain

    B Martínez-Poveda, J L Orgaz & B Jiménez

  5. Department of Pathology, Capio-Fundación Jimenez Díaz, Madrid, Spain

    S Zazo & F Rojo

  6. Department of Medical Oncology, Hospital del Mar-IMAS, and Cancer Research Program, IMIM-Hospital del Mar, Autonomous University of Barcelona, Barcelona, Spain

    A Rovira, J Albanell & F Rojo

  7. Department of Medical Oncology, La Paz University Hospital. IdiPAZ, Madrid, Spain

    C Belda-Iniesta

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  1. V Moncho-Amor
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Correspondence to R Perona.

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Moncho-Amor, V., Ibañez de Cáceres, I., Bandres, E. et al. DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer. Oncogene 30, 668–678 (2011). https://doi.org/10.1038/onc.2010.449

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