Dual-specificity Phosphatase 1 Deficiency Induces Endometrioid Adenocarcinoma Progression via Activation of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Pathway.

BACKGROUND: Previously, we reported that dual-specificity phosphatase 1 (DUSP1) was differentially expressed in endometrioid adenocarcinoma (EEA). However, the role of DUSP1 in EEA progression and the relationship between DUSP1 and medroxyprogesterone (MPA) are still unclear. METHODS: The expression of DUSP1 in EEA specimens was detected by immunohistochemical analysis. The effect of DUSP1 on cell proliferation was analyzed by Cell Counting Kit 8 and colony formation assay, and cell migration was analyzed by transwell assay. MPA-induced DUSP1 expression in EEA cells was measured by Western blot. RESULTS: DUSP1 expression was deficient in advanced International Federation of Gynecology and Obstetrics stage, high-grade and myometrial invasive EEA. In EEA cell lines (Hec1A, Hec1B, RL952, and Ishikawa), the DUSP1 expression was substantially higher in Ishikawa cells than in other cell lines (P < 0.05). Knockdown of DUSP1 promoted Ishikawa cells proliferation, migration, and activation of mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/Erk) pathway. MPA-induced DUSP1 expression and inhibited MAPK/Erk pathway in Ishikawa cells. CONCLUSIONS: Our data suggest that DUSP1 deficiency promotes EEA progression via MAPK/Erk pathway, which may be reversed by MPA, suggesting that DUSP1 may serve as a potential therapeutic target for the treatment of EEA.

[Relationship between the expression of dual specificity phosphatase-1 and the prognosis of endometrioid adenocarcinoma].

OBJECTIVE: To clarify the relationship between the expression of dual specificity phosphatase-1 (DUSP1) and the prognosis of endometrioid adenocarcinoma. METHODS: The expression of DUSP1 was determined by immunohistochemical staining in specimens from 81 patients with endometrial carcinoma undergoing surgical resection. The relationship between DUSP1 expression, clinicopathological factors and prognosis were further evaluated. RESULTS: In 81 endometrioid carcinoma samples, 59 (72.84%) cases were positive while 22 negative.Except for lymph node metastasis, the expression of DUSP1 was correlated with FIGO stage, tumor grade, myometrial invasion and the expressions of estrogen receptor (ER) and progesterone receptor (PR) (P < 0.05) .Kaplan-Meier analysis showed that patients with a positive DUSP1 expression had significantly prolonged 5-year disease-free survival rates of 98.2% and 76.0% respectively (P < 0.05). And COX regression analysis revealed that the expressions of DUSP1 and PR were independent prognostic indicators of endometrioid carcinoma, the HR (hazard ratio) of DUSP1 negative expression was 21.2.Spearman analysis further showed that the expression of DUSP1 was positively correlated with PR (r = 0.256, P < 0.05). CONCLUSION: DUSP1 may be a potential negative prognostic indicator for endometrioid adenocarcinoma.

Molecular subtypes identified by gene expression profiling in early stage endometrioid endometrial adenocarcinoma.

BACKGROUND: Early stage (FIGO stage I-II) endometrioid endometrial adenocarcinoma (EEA) is very common in clinical practice. However, patients with the early stage EEA show various clinical behaviors due to biological heterogeneity. Hence, we aimed to discover distinct classes of tumors based on gene expression profiling, and analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters. METHODS: Hierarchical clustering was performed for class discovery in 28 early stage EEA samples using a special cDNA microarray chip containing 492 genes designed for endometrial cancer. Correlations between clinicopathologic parameters and our classification were analyzed. And the significance analysis of microarrays (SAM) array was used to identify the signature genes according to the tumor grade and myometrial invasion. RESULTS: Three tumor subtypes (subtypes I, II and III) were identified by hierarchical clustering, each subtype had different clinicopathological factors, such as tumor grade, myometrial invasion status, and FIGO stage. Moreover, SAM analysis showed 34 up-regulated genes in high grade tumors, and 38 up-regulated genes and 1 down-regulated in deep myometrial invasive tumors. The overlap genes between these two high-risk factors were markedly up-regulated in subtype I, but down-regulated in subtype III. CONCLUSION: We have identified novel molecular subtypes in early stage EEA. Differential gene signatures characterize each tumor subtype, which could be used for recognizing the tumor risk and providing a basis for further treatment stratification.