DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer.
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.
Moncho-Amor
V
V
Instituto de Investigaciones Biomedicas CSIC/UAM, CIBER de Enfermedades Raras (CIBERER), IdiPAZ, Madrid, Spain.
Ibañez de Cáceres
I
I
Bandres
E
E
Martínez-Poveda
B
B
Orgaz
J L
JL
Sánchez-Pérez
I
I
Zazo
S
S
Rovira
A
A
Albanell
J
J
Jiménez
B
B
Rojo
F
F
Belda-Iniesta
C
C
García-Foncillas
J
J
Perona
R
R
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000556:secondary*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1