DUSP6, a tumor suppressor, is involved in differentiation and apoptosis in esophageal squamous cell carcinoma

Abstract

Dual-specificity phosphatase 6 (DUSP6), a specific negative feedback regulator of phosphorylated extracellular signal-regulated kinase, was found to play an important role in numerous types of solid tumors as a tumor suppressor. In this study, 64.2% (61/95) of esophageal squamous cell carcinoma (ESCC) specimens studied exhibited reduced DUSP6 protein expression, compared with 91% (81/89) of normal esophageal specimens that displayed moderate or strong DUSP6 protein expression in tissue microarray analysis. In total, 36.8% (7/19) of the tumor biopsies displayed at least two-fold downregulation of DUSP6 compared with their paired normal counterparts, by qPCR. Significant loss of DUSP6 was observed in EC9706 and KYSE150 ESCC cell lines by immunoblotting assay. Low DUSP6 protein expression was significantly associated with pathological grade in ESCC by immunohistochemistry (P<0.05). Treatment with 5-aza-2′-deoxycytidine restored DUSP6 expression in the two ESCC cell lines, and the expression varied according to the drug concentration. Methylation-specific PCR analysis showed methylation-specific products in the two ESCC cell lines. We observed significant differences in the early and total apoptotic proportion between the control and experimental groups of the two ESCC cell lines and their transfectants (P<0.001) by annexin/propidium iodide assay. The presence of cleaved PARP product, a marker of caspase-mediated apoptosis, expressed in the two pCMV-DUSP6 transfectants in marked contrast to the parental and pCMV-transfected EC9706 and KYSE150 cells, was observed by immunoblotting. Overall, our results support the role of DUSP6 as a novel candidate tumor suppressor gene in ESCC, which may be a potential prognostic marker for ESCC.

Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma

“…41 In ESCC, DUSP-6 was found to be down-regulated and to inhibit tumor progression. 52 We confirmed that DUSP-6 functions as a tumor suppressor in ESCC by inactivating the ERK/MAPK signaling pathway. Importantly, LINC01503 bound directly to ERK2 and prevented the dephosphorylation of ERK2 by DUSP-6.…”

Regulatory Roles of MAPK Phosphatases in Cancer

“…On the other hand, MKP-3 overexpression in ESCC and NPC cell lines resulted in reduced cancer cell proliferation and migration/ invasion in vitro , as well as reduced tumor growth in vivo ( 67 ). The tumor suppressive function of MKP-3 in ESCC was further supported by a recent study showing that MKP-3 expression was negatively correlated to pathological grade and that exogenous MKP-3 expression in ESCC cell lines markedly increased apoptosis in vitro ( 110 ).…”

Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA

“…As shown in Figure 4b , our analysis for 3ʹUTR-APAs included genes involved in different biological pathways ( Supplementary Table S1 ) with functions in DDR and cancer, such as small nuclear ribonucleoprotein polypeptide B (SNRPB2) [ 36 , 37 ], endoplasmic reticulum protein retention receptor 1 (KDELR1) [ 38 , 39 ]; Notch homolog 1 translocation-associated (NOTCH1) [ 40 , 41 ] and dual specificity phosphatase 6 (DUSP6) [ 42 , 43 ]. Consistent with the 3ʹREADS results ( Figure 1c ), the analysis of UV-induced 3ʹUTR-APA in the 0–0.5 h window indicated that each individual gene did not show a major change in the distal/proximal ratio.…”