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Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer

1
Department of Experimental Models of Human Diseases, Instituto de Investigaciones Biomédicas C.S.I.C./U.A.M, 28029 Madrid, Spain
2
The Francis Crick Institute, London NW1 1ST, UK
3
Cancer Epigenetics Laboratory, INGEMM, Hospital Universitario La Paz, 28046 Madrid, Spain
4
Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, 28046 Madrid, Spain
5
Departamento de Biotecnología-Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, 28223 Madrid, Spain
6
Bioinformatics, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
7
CIBER de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
8
Department of Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(8), 2036; https://doi.org/10.3390/ijms20082036
Received: 11 March 2019 / Revised: 9 April 2019 / Accepted: 22 April 2019 / Published: 25 April 2019
(This article belongs to the Special Issue Cell Targets and Toxicity)
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Abstract

DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of DUSP6. In agreement with these data, here we show that DUSP6 plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in epithelial to mesenchymal transition (EMT) in NSCLC-DUSP6 depleted cells. Data obtained in RNA-seq studies carried out in DUSP6 depleted cells identified EGFR, TGF-β and WNT signaling pathways and several genes such as VAV3, RUNXR2, LEF1, FGFR2 whose expression is upregulated in these cells and therefore affecting cellular functions such as integrin mediated cell adhesion, focal adhesion and motility. Furthermore, EGF signaling pathway is activated via ERK5 and not ERK1/2 and TGF-β via SMAD2/3 in DUSP6 depleted cells. In summary DUSP6 is a tumor suppressor in NSCLC and re-establishment of its expression may be a potential strategy to revert poor outcome in NSCLC patients. View Full-Text
Keywords: DUSP6; MKP3; tumor suppressor; ERK1/2; ERK5; tumorigenesis; EMT DUSP6; MKP3; tumor suppressor; ERK1/2; ERK5; tumorigenesis; EMT
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Moncho-Amor, V.; Pintado-Berninches, L.; Ibañez de Cáceres, I.; Martín-Villar, E.; Quintanilla, M.; Chakravarty, P.; Cortes-Sempere, M.; Fernández-Varas, B.; Rodriguez-Antolín, C.; de Castro, J.; Sastre, L.; Perona, R. Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2019, 20, 2036.

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