Prognostic value of dual-specificity phosphatase 6 expression in non-small cell lung cancer

Abstract

Dual-specificity phosphatase 6 (DUSP6/MKP-3) is a mitogen-activated protein kinase phosphatase that regulates extracellular signal-regulated kinases (ERKs) activity via feedback mechanisms, with an increasingly recognized role in tumour biology. The aim of this study was to explore the role of DUSP6 expression in the prognosis of human non-small cell lung cancer (NSCLC). DUSP6 expression levels were evaluated by real-time quantitative reverse transcription polymerase chain reaction (PCR) in 60 NSCLC samples from patients who underwent pulmonary resection at 12 de Octubre University Hospital. We performed a statistical analysis to investigate the correlation of DUSP6 expression and the clinical outcomes. We found that 66.7% of the tumour samples show the downregulation of DUSP6 at the messenger RNA (mRNA) levels compared to benign epithelial lung tissues and 55% of them show at least twofold downregulation of DUSP6 gene expression. Patients were classified into three groups according to their DUSP6 expression levels and those with very low levels (at least twofold downregulation) had the worst outcomes. Using the value of twice below the mean value in benign epithelial lung tissue as a cutoff, the overall survival of patients with very low DUSP6 levels was significantly lower than that in the rest of patients (31.9 ± 18.8 months vs. not reached, P = 0.049). This was most pronounced in adenocarcinoma histology and high-stage tumour samples. Our results suggest that DUSP6 gene expression in tumour samples may be a prognostic marker in NSCLC.

Overexpression of DUSP6 enhances chemotherapy-resistance of ovarian epithelial cancer by regulating the ERK signaling pathway

“…Consistent with our findings, studies of different types of solid tumors, including ovarian, breast, pancreatic, hepatocellular, esophageal, prostate, and lung carcinoma, reported that DUSP6 is underexpressed in highly proliferating tumor cells compared with normal cells [28,29,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] . This was thought to be due to DUSP6 acting as an ERK1/2specific negative regulator and suppression of the transcriptional activity of its downstream factors.…”

“…DUSP6-overexpressing SKOV3 cells also express lower levels of CyclinD3 (Figure 9). As DUSP6 is known to be a negative regulator of ERK1/2 [32][33][34][35][36][37] , we examined the levels of phosphor-ERK1/2 in these cells. Our study revealed that overexpression of DUSP6 decreased phospho-ERK1/2 levels in parallel with attenuated cyclin D3 expression (Figure 9b).…”

“…This was thought to be due to DUSP6 acting as an ERK1/2specific negative regulator and suppression of the transcriptional activity of its downstream factors. However, expression of DUSP6 increases as tumor proliferating activity decreases [32][33][34] . In lung cancer [35][36] and glioblastoma [44][45] , research has revealed that the proportion of cell in S phase is decreased and those in G1 phase increased in DUSP6overexpressing tumor cells.…”

Down‐regulation of dual‐specificity phosphatase 6, a negative regulator of oncogenic ERK signaling, by ACA‐28 induces apoptosis in NIH/3T3 cells overexpressing HER2/ErbB2

“…In cancer pathways, DUSPs generally play an antioncogenic role, by terminating the action of MAPKs, and the up ‐ regulation of DUSPs is considered to support the role of DUSP6 as a negative feedback regulator to restrain excess ERK signaling activation. Disruption of this feedback loop could therefore result in malignant transformation by providing cells with enhanced growth activity (Díaz‐García et al., 2015). Notably, however, DUSP6 knockdown by siRNA resulted in selective induction of apoptosis and impaired proliferation in A4‐15, but not in NIH/3T3 cells.…”

Onco-Golgi: Is Fragmentation a Gate to Cancer Progression?

“…Notably, hyperactivity of kinases in cancer is accompanied by down-regulation of phosphatases, which enzymatic action is directly opposite to that of kinases. The level of dual specificity phosphatase 6 (DUSP6) is reduced in lung cancer [85], and expression of dual-specificity phosphatase 2 (DUSP2) is low in breast, colon, lung, ovary, kidney, prostate, liver, and thyroid cancer [86]. It is important to note here that knockdown of both DUSP2 and DUSP6 significantly alters Golgi morphology [73].…”