TET1-GPER-PI3K/AKT pathway is involved in insulin-driven endometrial cancer cell proliferation.

Large amount of clinical evidence has demonstrated that insulin resistance is closely related to oncogenesis of endometrial cancer (EC). Despite recent studies showed the up-regulatory role of insulin in G protein-coupled estrogen receptor (GPER/GPR30) expression, GPER expression was not decreased compared to control when insulin receptor was blocked even in insulin treatment. The purpose of this study was to explore the possible mechanism by which insulin up-regulates GPER that drives EC cell proliferation. For this purpose, we first investigated the GPER expression in tissues of endometrial lesions, further explored the effect of GPER on EC cell proliferation in insulin resistance context. Then we analyzed the role of Ten-Eleven Translocation 1 (TET1) in insulin-induced GEPR expression and EC cell proliferation. The results showed that GPER was highly expressed in endometrial atypical hyperplasia and EC tissues. Mechanistically, insulin up-regulated TET1 expression and the latter played an important role in up-regulating GPER expression and activating PI3K/AKT signaling pathway. TET1 mediated GPER up-regulation was another mechanism that insulin promotes EC cell proliferation.

The role of the SDF-1/ CXCR7 axis on the growth and invasion ability of endometrial cancer cells.

PURPOSE: Stroma-derived factor-1 (SDF-1) and its receptor C-X-C chemokine receptor-4 (CXCR4) are involved in human endometrial carcinoma (EC) progression. CXCR7 is another important receptor of SDF-1 and has a higher affinity with SDF-1 compared with that of CXCR4. This paper aims to study the effects of the SDF-1/CXCR7 axis on the growth and invasion ability of EC cells. METHODS: CXCR7 expression was evaluated by quantitative RT-PCR, immunohistochemistry, immunocytochemistry and Western blotting in EC cell lines and 30 cases of primary EC tissue from patients. EC cell line proliferation and migration were assessed following knockdown of CXCR7 by MTT and transwell assays. RESULTS: The results showed that CXCR7 was highly expressed at both mRNA and protein levels in the EC cells and tissue. siCXCR7 effectively silenced CXCR7 in Ishikawa and AN3CA cells. Treatment with 17ß-oestradiol (17ß-E2) significantly increased the levels of CXCR7 and SDF-1 in Con, siCon and siCXCR7 treated Ishikawa. siCXCR7 persistently inhibited CXCR7 expression, even in cells treated with 17ß-E2. Moreover, in vitro functional analyses, silencing CXCR7 resulted in decreased proliferation in Ishikawa and AN3CA cells. Treatment with 17ß-E2 and SDF-1 significantly promoted the growth and migration in siCon treated Ishikawa and AN3CA. Interestingly, in response to 17ß-E2 and SDF-1 stimulation, siCXCR7 continuously inhibited the growth and invasion of Ishikawa and AN3CA cells. CONCLUSION: Our results indicate that SDF-1/CXCR7 plays a positive role in the proliferation and invasion of EC cells. CXCR7 inhibition treatment may provide a promising strategy for anti-tumour therapy for EC.

RNA sequencing analysis reveals apoptosis induction by hydrogen treatment in endometrial cancer via TNF and NF-κB pathways.

BACKGROUND: To evaluate the activity of hydrogen in endometrial cancer and elucidate its underlying molecular mechanisms. METHODS: Ishikawa, HEC1A and AN3CA cells were incubated in DMEM medium with or without hydrogen. RNA sequencing was used to explore the association of hydrogen treatment with signaling pathways and functional genes in endometrial cancer cells. The apoptotic rates of the three endometrial cancer cells were evaluated by fluorescein isothiocyanate (FITC) Annexin V and Annexin V-allophycocyanin (APC)/propidium iodide double staining. RESULTS: RNA sequencing analysis revealed that hydrogen induced TNF/NF-κB and apoptosis pathways in endometrial cancer cells. The gene sets between hydrogen treatment groups and non-treated groups were mapped in accordance with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms. Hydrogen treatment significantly increased the apoptotic rates of endometrial cancer cells. CONCLUSIONS: Taken together, our data indicate that hydrogen can serve as a therapeutic target for endometrial cancer via TNF/NF-κB pathway and apoptosis induction.

[Study of differential gene expression in different stage human endometrial cancer].

OBJECTIVE: To study the gene expression profile of different stage endometrial cancer and identify genes related to the progression and metastasis of endometrial cancer. METHODS: cDNA microarray was used to analyze the differentially expressed genes between different stage endometrial cancers. The hierarchical cluster analysis was applied to the gene expression profile of 32 endometrial cancers. RESULTS: Twelve differentially expressed genes were identified between different stage endometrial cancers. The conformity rate was 66% between the result of hierarchical cluster analysis and the operative-histological stages of International Federation of Gynecology and Obstetrics (FIGO). CONCLUSION: Genes related to the endometrial cancer progression and metastasis can be identified by differential gene expression profile with cDNA microarray and high-risk endometrial cancer may be distinguished before surgery by hierarchical cluster analysis.

[Relationship between CA125 half life during neoadjuvant chemotherapy and the optimal operation rate and prognosis in patients with advanced epithelial ovarian carcinoma].

OBJECTIVE: To investigate the relationship between the serum half life of CA(125) and the optimal operation rate and prognosis in patients with advanced epithelial ovarian carcinoma treated with neoadjuvant chemotherapy. METHODS: Clinical data of 39 patients who had undergone neoadjuvant chemotherapy were analyzed retrospectively. Patients were divided into two groups according to the serum half-life of CA(125), and the optimal operation rate and prognosis were compared. RESULTS: The optimal operation rate in patients with serum half-life >or= 20 days was significantly lower than that in patients with serum half-life < 20 days (29% vs 80%, P < 0.01). Cumulative survival was higher in patients with serum half-life < 20 days (P < 0.01). Serum half-life of CA(125) and tumor residual after operation were independent prognostic factors by COX model analysis. CONCLUSION: Serum half-life of CA(125) may indicate optimal debulking operation, and it is an independent prognostic factor in ovarian carcinoma patients treated with neoadjuvant chemotherapy.

[Establishment of the model of heterotopic uterine transplantation in syngeneic rats].

OBJECTIVE: To develop a surgical method for establishment of a heterotopic uterine transplantation model in syngeneic rats and evaluate its feasibility. METHODS: Thirty pairs of Wistar rats aged 8 - 10 weeks were used as donor and recipient. Heterotopic uterine transplantation was conducted, and the duration of the operation was recorded. The recipient rats were killed 7 days after surgery. The morphology of the transplanted uteri was evaluated. RESULTS: Thirty heterotopic uterine transplantations were conducted. The survival rate increased from 40% (6/15) in the first 15 pairs of recipient rats to 75% (12/15) in the last 15 pairs of recipient rats. Among the 18 living recipient rats, 15 transplanted uteri were viable. The viable rate of uterine transplantation was 83%. Compared with the first 15 pairs of rats, the duration of donor procedures, recipient procedures vascular anastomosis and the total time of the surgery decreased to (65 +/- 10) min, (89 +/- 22) min, (36 +/- 8) min and (154 +/- 23) min respectively in the last 15 pairs of rats. CONCLUSION: It is feasible to establish the model of heterotopic uterine transplantation in Wistar rats.

Management of type II unruptured cesarean scar pregnancy: Comparison of gestational mass excision and uterine artery embolization combined with methotrexate.

OBJECTIVE: This research was carried out to investigate the effectiveness, rationality, and safety of laparotomy management compared with uterine artery embolization (UAE) combined with methotrexate (MTX) for the treatment of deep implantation cesarean scar pregnancy (CSP II). MATERIALS AND METHODS: Data from 29 patients seen between June 2008 and February 2012 were retrospectively analyzed. The patients were divided into the surgery group and the UAE combined with MTX group according to the treatment they received. We compared the clinical characteristics and treatment outcomes between the two groups. RESULTS: The patients' clinical characteristics did not differ between the surgery group and the UAE combined with MTX group. However, the mean blood loss was decreased in the surgery group compared with the UAE combined with MTX group (90 ± 4.5 mL vs. 286 ± 5.2 mL, p < 0.05). No patients required blood transfusion in the surgery group, whereas two patients in the UAE combined with MTX group received blood transfusions. The length of time for the serum beta human chorionic gonadotropin (ß-HCG) level to normalize, the time required for the disappearance of the gestational mass, and the duration of hospital stay were significantly less in the surgery group than in the UAE combined with MTX group (13.7 ± 1.0 days vs. 40.7 ± 1.7 days, 7.1 ± 1.3 days vs. 135.4 ± 6.7 days, and 11.0 ± 1.2 days vs. 41.4 ± 3.2 days, respectively; p < 0.01). Although the treatment success rate did not differ significantly between the two groups, the success rate was 100% for the surgery group and 73% for the UAE combined with MTX group. CONCLUSION: Surgical treatment can remove gestational masses and allow wound repair. Moreover, laparotomy is available in almost all hospitals. Thus, surgery can be an effective and reasonable treatment for CSP II.

Regulation of epithelial-mesenchymal transition by homeobox gene DLX4 in JEG-3 trophoblast cells: a role in preeclampsia.

The pathogenesis of preeclampsia is unclear but is thought to be related to shallow trophoblast invasion. An invasive phenotype is acquired by trophoblasts through the process of epithelial-mesenchymal transition (EMT). We proposed that EMT in trophoblasts is deregulated in preeclampsia. The homeobox gene DLX4 plays an important role in epithelial-mesenchymal interactions during embryonic and placental development. To elucidate the role of DLX4 in trophoblast EMT and preeclampsia, we investigated the expression of DLX4 in preeclampsia-affected placentas and the effect of DLX4 on EMT in trophoblast-derived JEG-3 cells. DLX4 expression was downregulated in preeclampsia-affected placentas and hypoxic JEG-3 cells. Knockdown of DLX4 by RNA interference (RNAi) inhibited the motility and invasion ability of JEG-3 cells, decreased the expression of E-cadherin, and upregulated the expression of the E-cadherin repressor Snail. Our findings suggest that decreased expression of DLX4 leads to the pathogenesis of preeclampsia by inhibiting EMT in trophoblasts and provides new insight into the pathophysiological mechanism of preeclampsia.