Role of Dusp6 phosphatase as a tumor suppressor in non-small cell lung cancer.
journal contributionposted on 08.01.2020, 16:50 by Verónica Moncho-Amor, Laura Pintado-Berninches, Inmaculada Ibañez de Cáceres, Ester Martín-Villar, Miguel Quintanilla, Probir Chakravarty, María Cortes-Sempere, Beatriz Fernández-Varas, Carlos Rodriguez-Antolín, Javier de Castro, Leandro Sastre, Rosario Perona
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.
DUSP6EMTERK1/2ERK5MKP3tumor suppressortumorigenesisActin CytoskeletonAdenocarcinoma of LungAdherens JunctionsAnimalsCarcinogenesisCarcinoma, Non-Small-Cell LungCell AdhesionCell Line, TumorCell MovementCell ShapeDisease ProgressionDual Specificity Phosphatase 6Focal AdhesionsGene Expression Regulation, NeoplasticGenes, Tumor SuppressorHumansKaplan-Meier EstimateLung NeoplasmsMAP Kinase Signaling SystemMice, NudeTransforming Growth Factor betaCB0399 Other Chemical Sciences0604 Genetics0699 Other Biological SciencesChemical Physics