Shanghai Key Laboratory of Gynecologic Oncology

Shanghai, China

Shanghai Key Laboratory of Gynecologic Oncology

Shanghai, China
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Wang Y.,Shanghai JiaoTong University | Wang Y.,Shanghai Key Laboratory of Gynecologic Oncology | Wang Y.,Shanghai Health Bureau Key Disciplines and Specialties Foundation | Zhou J.,Shanghai JiaoTong University | And 13 more authors.
Biomaterials | Year: 2014

Systemic side effects and low aqueous solubility have limited the clinical use of cisplatin (CDDP) in ovarian carcinoma and have contributed to failures in developing effective drug delivery systems. In order to develop a novel drug delivery system with enhanced efficacy and minimal adverse effects, we exploited the properties of sodium alginate (SA) to synthesize CDDP-SA conjugate (CS), which is highly soluble and readily incorporated into liposomes (CS-PEG-Lip). Epidermal growth factor receptor (EGFR) is overexpressed in many ovarian cancers, therefore we modified EGF on the liposomes (CS-EGF-Lip) to specifically target EGFR-expressing tumors, thereby increasing the bioavailability and efficacy of CDDP. In vitro experiments confirmed that EGF-Lip selectively recognized EGFR-positive SKOV3 cells and effectively penetrated tumor spheroids. We demonstrated that CS-EGF-Lip possessed satisfactory size distribution and exhibited significantly improved encapsulation and loading efficiency. Furthermore, CS-EGF-Lip sustained release of CDDP in vitro, suggesting that CS-EGF-Lip may retain the antitumor activity of CDDP. Inhibition of proliferation and migration was also greater with CS-EGF-Lip compared to CDDP. In vivo xenograft experiments revealed that administration of CS-EGF-Lip enhanced delivery of CDDP into ovarian tumor tissues and improved the antitumor efficacy of CDDP, while reducing nephrotoxicity and body weight loss in mice. These results suggest that CS-EGF-Lip may offer a promising strategy for CDDP delivery in the treatment of EGFR-positive ovarian carcinoma or similar tumors, with enhanced efficacy and fewer adverse effects. © 2014 Elsevier Ltd.

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 | Year: 2015

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.

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 | Year: 2014

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.

Pu X.,Tongji University | Gu Z.,Shanghai JiaoTong University | Gu Z.,Shanghai Key Laboratory of Gynecologic Oncology | Wang X.,Tongji University
Archives of Gynecology and Obstetrics | Year: 2016

Purpose: To investigate the association between IL-6 gene polymorphism and cervical cancer risk, and the impact of multiple gene–gene interaction on cervical cancer risk based on a Chinese Han population. Methods: A total of 1088 women were selected, including 360 cervical cancer patients and 728 control subjects. Logistic regression model was used to examine the association between SNPs within IL-6 and cervical cancer risk. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the gene–gene interaction. Results: Cervical cancer risks were significantly higher in carriers of C allele of rs1800795 polymorphism than those with GG genotype (GC+CC versus GG), adjusted OR (95 % CI) 1.60 (1.24–2.19), and also significantly higher in carriers of G allele of rs2069837 polymorphism than those with AA (AG+GG versus AA), adjusted OR (95 % CI) 1.49 (1.19–2.07). GMDR analysis found a significant gene–gene interaction between rs1800795 and rs2069837 (p = 0.0010). Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 61.72 %. We also calculated the odds ratios and 95 % CI for this interaction, and we found that subjects with GC or CC of rs1800795 and AG or GG of rs2069837 genotype have the highest cervical cancer risk, compared to subjects with GG of rs1800795 and AA of rs2069837 genotype, OR (95 % CI) 3.35 (2.01–4.78). Conclusions: Minor allele of rs1800795 and rs2069837 and its interaction were associated with increased cervical cancer risk. © 2016 Springer-Verlag Berlin Heidelberg

Wang Y.,Shanghai JiaoTong University | Wang Y.,Shanghai Key Laboratory of Gynecologic Oncology | Liu P.,Shanghai JiaoTong University | Duan Y.,Shanghai JiaoTong University | And 14 more authors.
Biomaterials | Year: 2014

Good biocompatibility, specific tumor targeting, effective drug loading capacity and persistence in the circulation invivo are imperative prerequisites for the antitumor efficiency of nanoparticles and their further clinical application. In this study, APRPG (Ala-Pro-Arg-Pro-Gly) peptide-modified poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) nanoparticles (NP-APRPG) encapsulating inhibitors of angiogenesis (TNP-470) (TNP-470-NP-APRPG) were fabricated. TNP-470-NP-APRPG was designed to feature maleimide-PEG-PLA and mPEG-PLA as carrier materials, the APRPG peptide for targeting angiogenesis, PEG for prolonging circulation invivo and PLA for loading TNP-470. TNP-470-NP-APRPG was confirmed to be approximately 130nm in size with negative ζ'-potential (-14.3mV), narrow distribution (PDI=0.27) and spherical morphology according to dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. In addition, X-ray photoelectron spectra (XPS) analyses confirmed 7.73% APRPG grafting on the TNP-470-NP. Invitro, TNP-470-NP-APRPG exhibited effective inhibition of proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Similar findings were observed for the retardation of tumor growth in SKOV3 ovarian cancer-bearing mice, suggesting the significant inhibition of angiogenesis and antitumor efficiency of TNP-470-NP-APRPG. Moreover, no obvious toxic drug responses were observed. Further evidence obtained from the immunohistochemical examination demonstrated that the tumor growth inhibition was closely correlated with the high rate of apoptosis among endothelial cells and the effective blockade of endothelial cell proliferation. These results demonstrate that NP-APRPG is a promising carrier for delivering TNP-470 to treat ovarian cancer and that this approach has the potential to achieve broad tumor coverage in the clinic. © 2013.

Wang Y.,Shanghai JiaoTong University | Wang Y.,Shanghai Key Laboratory of Gynecologic Oncology | Liu P.,Shanghai JiaoTong University | Qiu L.,Shanghai JiaoTong University | And 8 more authors.
Biomaterials | Year: 2013

Construction on the nanoparticles with lower toxicity and specific tumor targeting properties is challenging and requires careful design of composition, size, physicochemical properties tailored for the nanoparticles. Here the epidermal growth factor (EGF) modified methoxy polyethylene glycol-polylactic-co-glycolic acid-polylysine (mPEG-PLGA-PLL) encapsulated cisplatin (CDDP) nanoparticles (CDDP-NPs-EGF) was prepared to for solving the toxicity of CDDP and improving therapeutic efficiency. The remarkable features of CDDP-NPs-EGF are increasing cytotoxicity that attribute to effective cell cycle arrest and high cell apoptosis in vitro. In vivo, the CDDP-NPs-EGF change drug distribution, decrease the nephrotoxicity of CDDP and improve significantly therapeutic efficiency without inducing obvious system toxicity, verifying its key role of the CDDP-NPs-EGF in lowering drug toxicity and enhancing the antitumor efficiency for SKOV3 cancer in mice. © 2013.

Zhou X.,Shanghai JiaoTong University | Zhou X.,Shanghai Key Laboratory of Gynecologic Oncology | Hu Y.,Shanghai JiaoTong University | Hu Y.,Shanghai Key Laboratory of Gynecologic Oncology | And 12 more authors.
PLoS ONE | Year: 2014

Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention. © 2014 Zhou et al.

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 | Year: 2012

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.

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 | Year: 2013

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.

Zhang N.,Renji Hospital | Zhang N.,Shanghai Key Laboratory of Gynecologic Oncology | Zhang N.,University of Sydney | Dai L.,Renji Hospital | And 6 more authors.
International Journal of Oncology | Year: 2013

Combination therapy with different anticancer drugs has been proven to be an effective strategy for the treatment of various types of cancers, including ovarian cancer. We have previously reported that FTY720 exhibited potent cytotoxic effects in ovarian cancer cells through the necrotic pathway, which differs from the killing effect of cisplatin (CDDP). In the present study, we report that the combination of FTY720 with CDDP yields an unexpected antagonistic effect towards the cytotoxicity of CDDP in a variety of ovarian cancer cell lines, including both CDDP-sensitive and-resistant cells. The antagonistic activity of FTY720 appears ascribable to its effect in autophagy induction. A significant increase in baseline autophagy was observed in CDDP-resistant ovarian cancer cells, compared with the sensitive cells. Blockade of autophagy by either a pharmacological inhibitor (3-MA) or siRNA-mediated knockdown of autophagic gene expression enhances CDDP-induced apoptotic cell death. Notably, by inhibiting autophagy, 3-MA can convert the combination of FTY720 with CDDP from an antagonistic into an additive effect towards killing ovarian cancer cells. Collectively, the findings suggest that a combination of an autophagy regulator with the CDDP-based regime could effectively modulate its efficacy for the treatment of ovarian cancer.

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