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Li D.,Shanghai JiaoTong University | Li D.,Shanghai Key Laboratory of Gynecologic Oncology | Ding C.-Y.,Peking University | Qiu L.-H.,Shanghai JiaoTong University | Qiu L.-H.,Shanghai Key Laboratory of Gynecologic Oncology
Gynecologic Oncology

Background Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear. Objective To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors. Methods Studies that provided an assessment of postoperative HRT use and prognosis or recurrence in EOC patients were included for analysis. Two reviewers independently evaluated the eligibility of identified studies and abstracted the data. A fixed effects model was used to pool study-specific estimates of hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs). Results Two randomized controlled trials (RCTs) and four cohort studies included 419 EOC survivors who used HRT and 1029 non-users. The aggregated HR of overall survival (OS) suggested that HRT use after surgery for EOC had a favorable impact on OS (HR = 0.69, 95% CI: 0.61-0.79), but when these studies were categorized into cohort study and RCT subgroups, not all of them demonstrated positive results (HR = 0.63, 95% CI: 0.49-0.81 and HR = 1.03, 95% CI: 0.58-1.83, respectively). The meta-analysis of EOC recurrence of three available studies demonstrated that postoperative HRT use was not associated with an increased risk of recurrence in EOC survivors (RR = 0.83, 95% CI: 0.64-1.07). This pattern also emerged in the subgroup analysis for the stage and type of HRT. Conclusions In EOC patients, postoperative HRT does not have a negative effect on overall survival and tumor recurrence. However, well-designed and large-scale RCTs are needed to verify this relationship in the future. © 2015 Elsevier Inc. Source

Dai L.,Shanghai JiaoTong University | Dai L.,Shanghai Key Laboratory of Gynecologic Oncology | Xia P.,Fudan University | Di W.,Shanghai JiaoTong University | Di W.,Shanghai Key Laboratory of Gynecologic Oncology
Cancer Investigation

Sphingosine 1-phosphate (S1P) is an important signaling regulator involved in tumor progression in multiple neoplasms. However, the role of S1P in the pathogenesis of ovarian cancer remains unclear. Herein, we summarize recent advances in understanding the impact of S1P signaling in ovarian cancer progression. S1P, aberrantly produced in ovarian cancer patients, is involved in the regulation of key cellular processes that contribute to ovarian cancer initiation and progression. Moreover, agents that block the S1P signaling pathway inhibit ovarian cancer cell growth or induce apoptosis. Hence, current evidence suggests that S1P may become a potential molecular target for ovarian cancer therapy. © 2014 Informa Healthcare USA, Inc. Source

Zhu J.,Shanghai JiaoTong University | Zhang S.,Shanghai JiaoTong University | Zhang S.,Shanghai Key Laboratory of Gynecologic Oncology | Gu L.,Shanghai JiaoTong University | And 2 more authors.

Wnt/β-Catenin signaling dysregulation is involved in tumorigenesis. Furthermore, epigenetic modification of the Dickkopf (DKK) family (DKK1-DKK4) has been shown to be important in Wnt signaling regulation. In this study, the role of DKK2, a Wnt antagonist, in epithelial ovarian cancer (EOC) was evaluated by examining the expression and methylation of DKK2 in SKOV3 and ES-2 ovarian cancer cell lines and 78 tissues collected from patients (50 ovarian carcinoma, 20 benign tumor and 8 normal ovarian tissues). DKK2 is highly downregulated in EOCs; however, DKK2 expression levels are higher in both normal tissues and benign tumors. In most cases of ovarian carcinoma, DKK2 is methylated, compared with the more common unmethylated form present in benign tumors and normal ovarian tissues. Additionally, DKK2 may be epigenetically silenced by methylation in higher grades and stages of EOC. Functional analysis revealed that overexpression of DKK2 suppressed malignant cell growth and invasion in SKOV3 and ES-2 cell lines. The expression of the downstream genes of Wnt signaling, including β-catenin, c-Myc and cyclin D1, was decreased in DKK2-transfected cells compared with mock cells. The expression of matrix metalloproteinase-2 and focal adhesion kinase were also decreased in DKK2 transfectants, supporting findings indicating inhibition of cell migration and invasion. This report provides novel indications that DKK2 is a unique hypermethylated target gene in EOC and that DKK2 may contribute to tumorigenesis in EOC through the Wnt/β-catenin signaling mechanisms. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

Zhang H.,Shanghai JiaoTong University | Zhang H.,Shanghai Key Laboratory of Gynecologic Oncology | Wang Q.,Shanghai JiaoTong University | Zhao Q.,Shanghai JiaoTong University | And 2 more authors.
Journal of Ovarian Research

Background: Epithelial ovarian cancer (EOC) is still a major gynecologic problem with poor 5 year survival rate due to distance metastases, despite routine surgery and chemotherapy. The precise underlying molecular mechanisms that trigger EOC migration and invasion are unclear. Recent studies suggest that the expression of microRNAs is widely dysregulated in ovarian cancer; and that they have evolved into tumorigenic processes, including cell proliferation, apoptosis and motility. Methods. The expression of miR-124 was assessed in clinical ovarian cancer specimens and cell lines using miRNA qRTPCR. The function of miR-124 on cell migration and invasion was confirmed in vitro through wound healing assay and transwell assay. Luciferase reporter assay was used to confirm target associations. Results: We showed that miR-124 is down-regulated in ovarian cancer specimens as well as in cell lines; and that low-level expression of miR-124 is much lower in highly metastatic ovarian cancer cells and tissues. Meantime, overexpression of miR-124 dramatically inhibits the motility of ovarian cancer cells in vitro and substantially suppresses the protein expression of SphK1, reported as an invasion and metastasis-related gene in human cancers, whose expression is markedly increased in both ovarian cancer cell lines and clinical samples, particularly in two highly metastasis cells, SKOV3-ip and HO8910pm as well as metastatic ovarian tumor tissues. Furthermore, SphK1 is identified as a direct target of miR-124, and knock-down of SphK1 in ovarian cancer cells, SKOV3-ip and HO8910pm, could mimic the inhibition of migration and invasion by miR-124, while re-introduction of SphK1 abrogates the suppression of motility and invasiveness induced by miR-124 in both cell lines. Conclusions: Our studies suggest a protective role of miR-124 in inhibition of migration and invasion in the molecular etiology of ovarian cancer, and a potentially novel application of miR-124 in the regulation of migration and invasion in EOC. © 2013 Zang et al.; licensee BioMed Central Ltd. Source

Dai L.,Shanghai JiaoTong University | Dai L.,Shanghai Key Laboratory of Gynecologic Oncology | Gu L.,Shanghai JiaoTong University | Gu L.,Shanghai Key Laboratory of Gynecologic Oncology | And 2 more authors.
Molecular Human Reproduction

MicroRNAs have recently been identified as regulators that modulate target gene expression and are suggested to be involved in the development and progression of endometriosis. This study was undertaken to analyze the expression level of microRNA-199a (miR-199a) in paired ovarian endometrioma and eutopic endometrium from women with endometriosis, and to investigate the contribution of miR-199a to the invasive capability of endometrial stromal cells (ESCs). Cell adhesion, migration and Matrigel invasion assays were carried out to measure the invasiveness of ESCs. Bioinformatics prediction, reporter gene assay, PCR, western blotting and ELISA were performed to identify miR-199a targets and related signaling pathways. The results showed that the expression level of miR-199a was lower in the eutopic endometrium from women with endometriosis, and even lower in the paired ovarian endometrioma, compared with the expression in normal controls. Moreover, ectopic expression of miR-199a attenuated ESC adhesion, migration and invasiveness. MiR-199a targeted and inhibited IkappaB kinase beta (IKKβ) in ESCs. Accompanied by IKKβ reduction, miR-199a suppressed nuclear factor-kappa B (NF-κB) pathway activation and interleukin-8 (IL-8) production in ESCs. All these findings suggest that miR-199a, down-regulated in endometriosis, attenuates the invasive capability of ESCs in vitro partly through IKK/NF-κB pathway suppression and reduced IL-8 expression. In conclusion, miR-199a could be involved in the pathogenesis of endometriosis. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. Source

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