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Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer
Verónica Moncho-Amor1,2, Laura Pintado-Berninches3, Inmaculada Ibañez de Cáceres4,5
1Department of Experimental Models of Human Diseases, Instituto de Investigaciones Biomédicas C.S.I.C./U.A.M, 28029 Madrid, Spain. Veronica.Moncho-Amor@crick.ac.uk.
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.
Insights
Dual-specific phosphatase DUSP6 acts as a tumor suppressor in non-small cell lung cancer (NSCLC). Low DUSP6 expression correlates with poor prognosis, impacting cell migration and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- DUSP6/MKP3 is a dual-specific phosphatase regulating ERK1/2 and ERK5.
- DUSP6 is increasingly recognized for its tumor suppressor functions.
- In silico analyses of GEO and TCGA databases indicate poor prognosis in NSCLC patients with low DUSP6 expression.
Purpose of the Study:
- To investigate the role of DUSP6 in non-small cell lung cancer (NSCLC).
- To elucidate the molecular mechanisms by which DUSP6 influences tumor progression.
Main Methods:
- In silico analysis of GEO and TCGA databases.
- RNA sequencing (RNA-seq) studies in DUSP6-depleted NSCLC cells.
- Analysis of gene expression, signaling pathways (EGFR, TGF-β, WNT), and cellular functions (migration, motility, adhesion).
Main Results:
- DUSP6 depletion in NSCLC cells leads to upregulation of epithelial to mesenchymal transition (EMT) genes.
- EGFR, TGF-β, and WNT signaling pathways are affected in DUSP6-depleted cells.
- Activation of EGF signaling via ERK5 and TGF-β signaling via SMAD2/3 occurs in DUSP6-depleted cells, impacting cell adhesion and motility.
Conclusions:
- DUSP6 functions as a tumor suppressor in NSCLC.
- Restoring DUSP6 expression may offer a therapeutic strategy for NSCLC patients with poor outcomes.
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