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To explore risk factors and develop a prediction model for ovarian metastasis in endometrial cancer (EC), as well as providing provide a reference for clinical ovarian preservation. We conducted a retrospective observational study enrolling 1496 EC patients having received complete staging surgery from Qilu Hospital of Shandong University from 2012 to 2018. These patients were randomly divided into two cohorts: training cohort (n = 1046) and validation cohort (n = 448). A nomogram prediction model was developed based on univariate, least absolute shrinkage and selection operator (Lasso), and multivariate logistic regression. Then, the nomogram model’s performance was evaluated in discrimination, calibration, and clinical utility three aspects. Parametrium invasion, lymph node metastasis, and oviduct metastasis were finally contained in the nomogram prediction model. The AUC of the model in the training cohort was 0.85 compared with 0.72 in the validation cohort. It also behaved well in calibration and had good clinical utility. With a threshold probability of 20% ~ 80%, the nomogram increased the net benefit by 0 ~ 13.6 per 100 patients than surgery for all patients upon validation. We develop a nomogram with good performances for predicting ovarian metastasis in EC patients, which may help clinicians identify candidate patients appropriate for ovarian preservation in premenopausal EC patients.

Qianhan Lin,1,2,* Xiaoxue Ma,1,2,* Shunxue Hu,3 Rui Li,1,2 Xuan Wei,1,2 Bing Han,1 Yanhui Ma,1 Peishu Liu,1,2,4 Yingxin Pang1,2,4 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of China; 2Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, 250012, Shandong, People’s Republic of China; 3Department of Pathology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of China; 4Shandong Engineering Laboratory for Urogynecology, Jinan, 250012, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peishu LiuDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of ChinaTel +8618560081988Email peishuliu@126.comYingxin PangDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of ChinaTel +8618560081127Email yingxinpang@126.comPurpose: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. NCL expression levels have been linked to the outcomes of various malignancies, but the clinical value of NCL in patients with endometrial carcinoma (EC) remains unclear. Here, the expression of NCL in EC tissues and its associations with patient outcomes were assessed.Patients and Methods: Data on NCL mRNA expression in EC and adjacent nonneoplastic tissues from The Cancer Genome Atlas (TCGA) were analyzed. In addition, NCL protein expression in 82 endometroid endometrial adenocarcinoma tissues and 15 non-malignant tissues was detected by immunohistochemistry.Results: Elevated NCL expression was markedly correlated with serous endometrial carcinoma (P< 0.001), advanced stage (P=0.029), and grade 3 (P< 0.001). High NCL levels were associated with poorer overall survival (OS) and disease-free survival (DFS) compared with intermediate or low NCL levels (OS: P=0.001, DFS: P=0.006). The multivariate Cox proportional hazards model showed that NCL expression was an independent poor prognostic factor for DFS (HR=1.282, CI=1.027– 1.601, P=0.028). A similar correlation between high expression levels of NCL and unfavorable DFS was found in endometrioid endometrial adenocarcinoma (HR=1.411, CI=1.083– 1.840, P=0.011). Positive extra-nuclear NCL expression (HR=3.377, 95% CI=1.029– 11.186, P=0.046) and low nuclear NCL expression (HR=0.233, 95% CI=0.068– 0.796, P=0.020) were independent prognostic factors for DFS in endometrioid endometrial adenocarcinoma.Conclusion: Heterotopic NCL is a potential prognostic biomarker for EC. Inhibiting the distribution of NCL from the nucleus to the cytoplasm and membrane may be a promising therapeutic strategy to improve outcomes in patients with EC with high NCL expression.Keywords: nucleolin, endometrial carcinoma, prognostic marker, TCGA

Background Nuclear protein 1 (NUPR1) plays a critical role in the development and progression of various types of human cancers. However, the role and mechanism of NUPR1 in ovarian cancer have not been elucidated. The purpose of this study was to investigate the effect of NUPR1 on ovarian cancer in vivo and in vitro. Materials and Methods Through the pretreatment of ovarian cancer cell lines, including A2780 and SKOV3 cells, the expression of NUPR1 was detected by RT-PCR and Western blot assays. When NUPR1 was overexpressed and knocked down in A2780 cells and overexpressed in SKOV3 cells, the MTT assays, colony formation assays and EdU assays were used to detect cell proliferation. Furthermore, cell invasion and migration ability were detected with the transwell assays. Cell cycle and apoptosis of A2780 cells after small interfering RNA-NUPR1 (siRNA-NUPR1) were detected by flow cytometry assays. Finally, the effect of NUPR1 gene silencing on the growth of ovarian cancer was evaluated by tumor xenograft experiment in vivo. Results The expression of NUPR1 protein in A2780 cells was significantly higher than that in ovarian surface epithelium (OSE) cells (P < 0.05). The results showed that downregulation of NUPR1 gene expression significantly inhibited the proliferation, migration and invasion ability of A2780 cells, and increased apoptosis of A2780 cells, which expressed relatively high levels of NUPR1. And the expression of apoptosis-related proteins caspase 3, caspase 9 and Bax was upregulated when NUPR1 was knocked out, while the expression of anti-apoptotic proteins of Bcl-2 and Bcl-xl was downregulated. At the same time, the opposite results were observed when NUPR1 was overexpressed in A2780 and SKOV3 cells. Notably, the effect of NUPR1 overexpression in A2780 cells could be partially or completely eliminated by treatment with the AKT inhibitor LY294002. In addition, NUPR1 knockdown could effectively inhibit tumor growth of mice in vivo. Conclusion In summary, NUPR1 has a carcinogenic effect in ovarian cancer, and the oncogenic effect of NUPR1 in ovarian cancer may be achieved by the AKT pathway.

Non-gestational ovarian choriocarcinoma (NGOC) is a rare malignant germ cell tumor. Through literature review and cases collection, we aim to analyze prognostic factors for NGOC and summarize its clinicopathological characteristics to guide the individualized treatment. We searched PubMed database, Cochrane library, and Google Scholar for cases published between January 1, 1967 and July 31, 2018 using various search terms. We retrieved patients’ clinicopathological characteristics, treatment, and prognosis information from included studies. These patients were divided into two groups: died (case group) or alive (control group) group. We summarized and compared their clinical (age, symptoms, R0 resection, serum HCG levels, chemotherapy regimen) and pathological (pure vs non-pure type, tumor size, tumor location, metastasis sites, stage) features by statistical analysis. Only 39 patients were retrieved from 36 studies in total. The median age was 30 years (range 12- to 65-years old). The peak incidence was in the adolescent age 12–25 years. Median follow-up was 20.3 months (range 1–84 months). 9 (23%) patients died; 24 (62%) patients were alive; 6 (15%) were lost to follow-up. Upon univariate analysis, we found age had a poor impact on overall survival (OS) in NGOC, HR − 0.057, 95% CI − 0.111 to − 0.004. Pure type NGOC has a better OS than mixed type, HR − 2.621, 95% CI − 4.577 to − 0.666. R0 resection is a good prognostic factor for OS, HR 2.967, 95% CI 0.709–5.224. Clinicians should try to achieve R0 resection to improve the prognosis for NGOC patients even among advanced patients.

Xue Zhang,1– 3 Xuan Wei,1– 3 Gaigai Bai,1– 3 Xueyao Huang,1– 3 Shunxue Hu,4 Hongluan Mao,1– 3 Peishu Liu1– 3 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 2Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 4Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Hongluan Mao; Peishu LiuDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong, People’s Republic of ChinaEmail hongluanmao@126.com; peishuliu@126.comPurpose: Ovarian cancer is the most lethal gynecologic malignancy. Resistance to platinum-based chemotherapy affects the overall survival of patients. This study used an integrated bioinformatics to find the poorly understood molecular mechanisms underlying platinum resistance in ovarian cancer.Methods: Based on the RNA-seq data of tissues in The Cancer Genome Atlas (TCGA) and RNA-seq data of cells from the Cancer Cell Encyclopedia (CCLE), we integrated differentially expressed genes (DEGs) in ovarian cancer tissue and cells. After screening for DEGs related to platinum resistance, we conducted survival analysis and built protein interaction networks to identify genes that may affect prognosis and interact with each other. Least absolute shrinkage and selection operator (Lasso) regression analysis was used to construct a predictive model. Immunohistochemistry and Western blot were used to validate the results. Finally, gene set enrichment analysis (GSEA) was performed on the expression of genes individually.Results: We found that ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) interacted with each other and could predict resistance to platinum-based therapy, correlating negatively with prognosis. Moreover, we constructed a predictive model based on nine genes, including ATP1A2 and CASQ2. Immunohistochemistry and Western blot validated the upregulation of these genes in ovarian cancer tissue samples and cell lines. The immunohistochemistry results also confirmed the prognostic value of ATP1A2, CASQ2 and RYR2. GSEA predicted that ATP1A2, CASQ2 and RYR2 may act on the KRAS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.Conclusion: ATP1A2, CASQ2 and RYR2 were highly expressed in platinum-resistant ovarian cancer. ATP1A2 and CASQ2 were related to the prognosis of platinum-resistant ovarian cancer patients. These genes might act on KARS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.Keywords: ovarian cancer, platinum resistance, prognosis, metabolic reprogramming, calcium homeostasis

Background Bromodomain and extra-terminal domain inhibitors like JQ1 have proved to be promising epigenetic agents for the treatment of malignant ovarian carcinoma. However, the resistance of ovarian cancer cells to BET inhibitors has not been elucidated. In this study, we investigated the potential mechanisms underlying the resistance of ovarian cancer cell lines to the BET inhibitor JQ1. Materials and methods We evaluated the apoptotic and proliferative response of four ovarian cancer cell lines to JQ1. The cell lines were designated as resistant (A2780 and HO-8910) and sensitive groups (SKOV-3 and HEY). Further experiments detected the different levels of JQ1-induced autophagy. Anti-tumour effect of the combination of JQ1 and autophagy inhibitors was tested both in vitro and in vivo. Results In the JQ1-sensitive group, JQ1 effectively inhibited proliferation and apoptosis in a concentration-dependent manner. Conversely, JQ1 showed modest inhibition of proliferation and negligible apoptosis in the resistant group. We detected increased LC3-II lipidation, autophagosome formation, upregulation of Beclin-1 and ATG5, and downregulation of P62/SQSTM1 in the resistant group. Inhibition of JQ1-induced autophagy by pharmacologic inhibitors 3-MA and CQ enhanced the inhibition of proliferation and significantly increased the apoptosis in the JQ1-resistant group, which was also verified by in vivo experiments, indicating that JQ1-induced autophagy played a cytoprotective role. Inactivation of Akt (Ser473)/mTOR(Ser2448) pathway was associated with JQ1-induced autophagy in the resistant group. Overexpression of Akt1 suppressed autophagy and increased the anti-tumour effect of JQ1. Conclusion These findings revealed that JQ1-induced pro-survival autophagy might be a potential mechanism in the resistance of ovarian cancer cells to BET inhibition by JQ1. Combination of JQ1 and autophagy inhibitors could be an effective therapeutic strategy for overcoming BET inhibitor resistance in ovarian cancer.

Yolk sac tumor (YST) is a malignant tumor derived from germ cells and usually occurs in the gonads. Extra-gonadal YST is most commonly seen in the vagina of children, but rarely in the cervix, vulva and endometrium. Primary YST of endometrium was extremely rare, standard treatment was still controversial and no guideline was established so far. The aim of the present study was to provide a comprehensive understanding and systematic thought for the management of primary YST of endometrium. A systematic research of the literature was conducted in Scopus, PubMed database and Cochrane Library, including case reports and case series. We summarized clinical characteristics, treatments and prognosis of all collected cases. We collected data regarding patients, serum AFP level, initial symptoms, surgical information, postoperative chemotherapy and radiotherapy. A new case was also discussed. We found only 26 cases have been reported previously. We reported a new case of primary endometrial YST in a 27-year-old woman, and in this case, we creatively performed bilaterally ovarian preservation and used DC (docetaxel and carboplatin) regimen of postoperative chemotherapy, we achieved a relatively good prognosis during the follow-up period of 14 months. Primary YST of endometrium, kind of highly malignant germ cell tumors, was extremely rare, of which initial symptom is usually abnormal vaginal bleeding. Standard treatment was still controversial and no guideline was established so far. Surgery combining with postoperative chemotherapy was considered effective for treatment of primary endometrial YST. Decision on whether to preserve ovaries in young patient with early stage needs careful consideration, comprehensive preoperative assessment and full communication. Intraoperative biopsy and strict postoperative follow-up are recommended. However, standard chemotherapy regimen and feasibility of postoperative radiotherapy remains to be discussed.

Curcumin (Cur), a yellow-colored dietary flavor from the plant (Curcuma longa), has been demonstrated to potentially resist diverse diseases, including ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with curcumin resistance in ovarian cancer still remains unclear. The aim of our study was to investigate the effects of curcumin on autophagy in ovarian cancer cells and elucidate the underlying mechanism. In our study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), EdU proliferation assay and colony-forming assay were used to assess cell viability. Apoptosis was detected by western blot and flow cytometric analysis of apoptosis. Autophagy was defined by both electron microscopy and immunofluorescence staining markers such as microtubule-associated protein 1 light chain 3 (LC3). Plasmid construction and shRNA transfection helped us to confirm the function of curcumin. Curcumin reduced cell viability and induced apoptotic cell death by MTT assay in human ovarian cancer cell lines SK-OV-3 and A2780 significantly. Electron microscopy, western blot and immunofluorescence staining proved that curcumin could induce protective autophagy. Moreover, treatment with autophagy-specific inhibitors or stable knockdown of LC3B by shRNA could markedly enhance curcumin-induced apoptosis. Finally, the cells transiently transfected with AKT1 overexpression plasmid demonstrated that autophagy had a direct relationship with the AKT/mTOR/p70S6K pathway. Curcumin can induce protective autophagy of human ovarian cancer cells by inhibiting the AKT/mTOR/p70S6K pathway, indicating the synergistic effects of curcumin and autophagy inhibition as a possible strategy to overcome the limits of current therapies in the eradication of epithelial ovarian cancer.

High-grade ovarian serous carcinoma (HGS-OvCa), a type of ovarian cancer with poor prognosis due to distant metastasis, is urgently in need of new therapeutic targets. microRNAs (miRNAs), a class of small noncoding RNAs, perform significant roles in tumor progression. Mounting evidence has revealed the aberrant expression of miRNA in various cancers, one of which is HGS-OvCa. Present study planned to investigate that miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis. Upregulation of miR-301b-3p was uncovered in HGS-OvCa tissues and cell lines, and was identified to be associated with metastasis. The Kaplan-Meier analysis confirmed the association of miR-301b-3p with poor prognosis of HGS-OvCa patients. Transwell assay validated the oncogenic effect of miR-301b-3p on migration and invasion of HGS-OvCa cells. Cytoplasmic polyadenylation element binding protein 3 (CPEB3) was then identified as a target of miR-301b-3p. It was also discovered that CPEB3 was downregulated in HGS-OvCa tissues and cell lines. The Spearman correlation curve presented the negative correlation of CPEB3 expression with miR-301b-3p. Furthermore, rescue assays proved that miRNA-301b-3p regulated the invasion and migration through CPEB3. Western blot and qRT-PCR analysis showed that miRNA-301b-3p induced epidermal growth factor receptor and downstream metastasis-related proteins, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2), through CPEB3. To be concluded, these results indicated that miRNA-301b-3p accelerated migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.

Background. GA-binding protein A (GABPA), a transcription factor, is broadly involved in physiological and pathological processes. Several studies have investigated the relationship between GABPA expression level and outcomes of various malignancies. However, the function and clinicopathological significance of GABPA in endometrial carcinoma (EC) remain obscure. Methods. The GABPA mRNA expression in EC tissues and adjacent nonneoplastic tissues in the TCGA database was involved in our study. The protein expression of GABPA in 107 EC tissues and 15 normal endometrial tissues was detected by immunohistochemistry. Results. The GABPA expression was significantly downregulated in EC tissues compared with its expression in normal tissues ( P < 0.001 ). The expression of GABPA was markedly correlated with type II EC ( P < 0.01 ) and grade 3 EC ( P < 0.05 ). A tendency has been observed that patients with low GABPA levels had relatively poorer overall survival (OS) ( P = 0.036 ) and disease-free survival (DFS) ( P = 0.016 ) than patients with high GABPA levels. The multivariate Cox proportional hazard model showed that lower expression of GABPA was an independent poor prognostic factor for OS ( P = 0.043 ) and DFS ( P = 0.045 ). Similar correlation between low expression levels of GABPA and unfavorable prognosis has also been found in type II or grade 3 EC. IHC analysis showed EC tissues had low expression of GABPA, which indicated relatively poor prognosis. Moreover, we identified that the GABPA mRNA expression was negatively correlated with its methylation level ( R = − 0.2512 , P < 0.001 ) which is one of the mechanisms for the silencing of GABPA gene. Conclusion. GABPA may act as an independent predictor of clinical prognosis and serve as a potential target gene for EC therapy.

Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin is the first-line chemotherapy to treat ovarian cancer patients along with debulking surgeries, its efficacy is limited due to the high incidence of cisplatin resistance. ATP citrate lyase (ACLY) has been shown to be a key metabolic enzyme and is associated with poor prognosis in various cancers, including ovarian cancer. Nevertheless, no studies have probed the mechanistic relationship between ACLY and cisplatin resistance.Methods: Survival analysis was mainly carried out online. Bioinformatic analysis was performed in R/R studio. Proliferative activity was measured by MTT and colony formation assays. Cell cycle and apoptosis analysis were performed by flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP was generated by exposing A2780 to cisplatin at gradually elevated concentrations. MTT assay was used to calculate IC50 values of cisplatin. A xenograft tumor assay was used test cell proliferation in vivo.Results: Higher expression of ACLY was found in ovarian cancer tissue and related to poor prognosis. Knockdown of ACLY in A2780, SKOV3, and HEY cells inhibited cell proliferation, caused cell-cycle arrest by modulating the P16–CDK4–CCND1 pathway, and induced apoptosis probably by inhibiting p-AKT activity. Bioinformatic analysis of the GSE15709 dataset revealed upregulation of ACLY and activation of PI3K–AKT pathway in cells with acquired cisplatin resistance, in line with observations on A2780/CDDP cells that we generated. Knockdown of ACLY alleviated cisplatin resistance, and works synergistically with cisplatin treatment to induce apoptosis in A2780/CDDP cells by inhibiting the PI3K–AKT pathway and activating AMPK–ROS pathway. The ACLY-specific inhibitor SB-204990 showed the same effect. In A2780/CDDP cells, AKT overexpression could attenuate cisplatin re-sensitization caused by ACLY knockdown.Conclusions: Knockdown of ACLY attenuated cisplatin resistance by inhibiting the PI3K–AKT pathway and activating the AMPK–ROS pathway. These findings suggest that a combination of ACLY inhibition and cisplatin might be an effective strategy for overcoming cisplatin resistance in ovarian cancer.

To first investigate on the association between BRCA mutations and endometrial carcinoma. To first evaluate the contribution of tamoxifen use and risk-reducing bilateral salping-oophenrectomy (BSO) on endometrial carcinoma in BRCA carriers. A systematic search of electronic databases including the PubMed and EMBASE was conducted to identify publications exploring the association between BRCA mutations and endometrial carcinoma. Finally, single rate meta-analysis and diagnostic meta-analysis were performed. 11 retrospective studies and 3 prospective studies were included in the meta-analysis, single rate meta-analysis was performed on retrospective studies and prospective studies respectively. We got that incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Diagnostic meta-analysis performed on prospective studies found that tamoxifen increased incidence of endometrial carcinoma in BRCA carriers. The incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035 according to present studies, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Tamoxifen use is a certain risk factor for subsequent endometrial carcinoma, while history of breast cancer or risk-reducing BSO is not associated with incidence of follow-up endometrial carcinoma. The necessity and rationality of prophylactic hysterectomy for BRCA carriers remained to be discussed.

As one of the main gynecological cancers, ovarian cancer (OC) has an unfavourable outcomes owing to its high recurrence and metastasis rate. Our previous studies have revealed that LINC01296 functions as an oncogene in OC, but the underlying mechanism has not been explored. The aim of this paper was to further investigate that how LINC01296 plays a role in OC. Through online software prediction, miR-29c-3p has been discriminated as the target miRNA of LINC01296 for further research, and subsequent luciferase assay confirmed bioinformatics prediction. Then the data obtained from the two databases (GSE119055 and GSE83693) were analyzed by GEO2R for differential gene analysis. The results indicated that the miR-29c-3p was lowly expressed in OC tissues than that in normal ovarian tissues, and its expression in recurrent OC tissues was lower than that in primary OC tissues. Simultaneously, Kaplan-Meier survival analysis illustrated that the lower expression of miR-29c-3p was interrelated to unfavourable outcomes of OC. Further, the qRT-PCR data revealed that the miR-29c-3p expression in OC cell lines (SKOV-3 and OVCAR-3) was markedly declined than that in normal control cells (IOSE80). Subsequently, the functional experiments, such as CCK8, colony formation and Transwell assays, prompted that inhibition of miR-29c-3p can obviously increase the proliferation, invasion and migration of OVCAR3 and SKOV3 cells compared with control group, while downregulation of LINC01296 showed an opposite result. It is worth noting that downregulation of LINC01296 can reverse the effect of miR-29c-3p suppression on OC cells. Finally, we detected the changes of EMT-related proteins by western blot experiment, and reached a similar conclusion that knockdown of LINC01296 reversed the EMT caused by miR-29c-3p inhibition. In sum up, the cancer-promoting function of LINC01296 was achieved by regulating the expression of miR-29c-3p, and LINC01296/miR-29c-3p axis mediates the mechanical regulation of EMT in OC cells, hoping to provide the novel biomarkers and possibilities for OC therapy.

Background: Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug-resistance is the primary cause of treatment failure. Objective: Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method: CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results: Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drugresistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion: This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug-resistance genes.

This study aimed to explore the roles of miRNA-34a (miR-34a) in ovarian cancer (OC) cells and uncover possible mechanisms. The proliferation of OC cells was measured with an MTT assay and soft agar colony formation assay. TargetScan analysis, real-time PCR, and a luciferase reporter assay were used to demonstrate the downstream target of miR-34a in OC cells. HDAC1 expression levels were detected by immunoblot analysis. miR-34a inhibited the proliferation of SKOV3 and OVCA433 cells and enhanced cisplatin sensitivity in cisplatin-resistant SKOV3cp cells. The results of TargetScan analysis, real-time PCR, and luciferase reporter assay confirmed that miR-34a downregulated HDAC1 expression by directly targeting the 3′-UTR of HDAC1 mRNA. The overexpression of HDAC1 decreased cisplatin sensitivity and promoted proliferation in OC cells. MTT assay and soft agar colony formation assay showed that HDAC1 overexpression blocked the suppressive effects of miR-34a on SKOV3 cell proliferation. In addition, treatment with the miR-34a mimic partially recovered the cisplatin sensitivity of SKOV3cp cells, whereas HDAC1 overexpression blocked the above phenomena caused by treatment with the miR-34a mimic. miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

X-linked inhibitor of apoptosis‑associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that may reverse the anti‑apoptotic effect of XIAP. Previous studies have revealed that XAF1 serves an important role in cancer angiogenesis. Vasculogenic mimicry (VM) describes the formation of fluid‑conducting channels by highly invasive and genetically dysregulated tumor cells. VM is critical for tumor blood supply and is associated with aggressive actions and metastasis. The aim of present study was to investigate the potential association between XAF1 expression with VM of ovarian cancer, and evaluate the role of XAF1 in tumor cell migration and invasion of SKOV3 cells. VM structure and XAF1 expression were detected in 94 tissue samples of advanced epithelial ovarian cancer (EOC). Invasion and migration of the SKOV3 human ovarian carcinoma cell line were identified by Transwell assay. It was revealed that the presence of VM was associated with high grade advanced ovarian cancer. Reduced XAF1 expression was significantly associated with presence of VM. Overexpression of XAF1 significantly reduced invasion and migration of SKOV3 cells, and inhibited vascular endothelial growth factor protein expression. Furthermore, vasculature was suppressed by overexpression of XAF1 in vivo in xenograft models. In conclusion, XAF1 expression was associated with VM in ovarian cancer, suggesting a potential role of XAF1 in the formation of VM in EOC. These findings may facilitate the development of novel therapeutic agents for the treatment of ovarian cancer.

Background: To identify the level of periostin in serum and peritoneal washing fluids (PWF) from women with and without endometriosis, as well as to explore the potential of periostin as a biomarker of endometriosis. Methods: Samples were obtained from 184 women with and without endometriosis. Concentrations of periostin in PWF and blood were measured by enzyme-linked immunosorbent assay. Results: Levels of periostin both in serum and PWF were notably elevated in women with endometriosis in both the proliferative and secretory phase. Combined with dysmenorrhea and infertility, two potential covariates, the serum periostin had a sensitivity of 75.00%, specificity of 65.00%, and area under the curve (AUC) of 0.774, whereas the PWF periostin had a sensitivity of 94.23%, specificity of 90.00%, and AUC of 0.967 for the diagnosis of endometriosis. Conclusion: Serum and PWF periostin concentrations may be new potential biomarkers for endometriosis, especially when combined with dysmenorrhea and infertility.

Introduction Rudimentary horns and unicornuate uteri, 2 types of Mullerian duct abnormalities, often lack obvious symptoms. Ultrasonography (US) and magnetic resonance imaging (MRI) are alternative examinations but have low accuracy. Full-term rudimentary horn pregnancies are rather rare but life-threatening. Patient concerns A 30-year-old Chinese woman complained of lower abdominal pain one year after a full-term unicornate uterus pregnancy and a rudimentary horn pregnancy successively. Diagnosis Uterine dysplasia (right rudimentary uterine horn and left unicornate uterus), hematometra and right fallopian tube effusion were diagnosed. Interventions We performed laparoscopic hysterectomy (rudimentary horn), right salpingectomy, pelvic adhesion release and hysteroscopy. Outcomes The patient has not complained of specific discomfort during the one-year follow-up so far. Conclusion The reported case was a rare full-term rudimentary horn pregnancy. The degree of development of the rudimentary horn, such as the endometrial function, muscle layer thickness, and uterine shape and size, is closely related to pregnancy outcome. The rudimentary horn with a functional endometrium must be disposed of once it is definitely diagnosed. Pregnancy in the rudimentary horn with a weak muscular layer should be treated as soon as possible. Detailed and scientific prenatal examination is important.

Src is a known proto-oncogene and its aberrant activity is involved in a variety of cancers, including ovarian cancer, whereas the regulatory mechanism of Src has not been fully clarified. In this study, we identified tripartite motif-containing (TRIM) 50 as a novel negative regulator of Src protein. Our data showed that TRIM50 directly interacted with SH3 domain of Src via its B-box domain; and TRIM50 reduced Src stability by inducing RING domain-dependent K48-linked poly-ubiquitous modification. We further demonstrated that TRIM50 acted as a tumor suppressor in ovarian cancer cells by its negative regulation of Src protein. In vivo animal model verified that TRIM50 inhibited the xenograft tumor growth of ovarian cancer by suppressing Src protein. Clinical investigation showed that expression of TRIM50 in clinical specimens was inversely correlated with the clinical stages, pathology grades and lymph node metastatic status of the patients, which indicated the involvement of aberrant TRIM50 expression in disease progression. Further analysis verified the negative correlation between TRIM50 and Src expression in clinical specimens. Altogether, we identified TRIM50 as a novel suppressor of Src protein, and demonstrated that TRIM50 inhibited ovarian cancer progression by targeting Src and reducing its activity, which provided a novel therapeutic strategy for Src over-activated cancers by positive regulation of TRIM50.

Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its chemoresistance and frequent late diagnosis, and suggesting that a more effective treatment approach is needed. Lysyl oxidase (LOX) is involved in important biological processes such as gene regulation, cell signaling and cell motility, its deregulation contributing to tumor formation and development. Although it is known that LOX is involved in proliferation, migration and invasion in several types of tumors, studies of LOX in ovarian cancers are scarce. To explore the molecular regulation mechanisms in ovarian cancer tumorigenesis, the expression change and the function of LOX was confirmed in ovarian tissues and cells, which suggested that LOX is a tumor suppressor gene. To further understand how LOX expression is regulated in ovarian cancer, microRNAs(miRNAs) were considered because of their role in post-transcriptional regulation of many genes. Recent work has described differential expression of mature miRNAs in human cancers. Bioinformatics prediction which was used to find the appropriate miRNA regulating LOX, revealed that miR-29b regulates LOX protein level via its binding site on the 3'UTR of LOX mRNAin ES-2 cells, a human ovarian clear cell carcinoma cell line. miR-29b knockdown inhibited proliferation and invasion in ES-2 cells. Taken together, these findings suggest that influencing LOX regulation bychanging the level of miR-29b expression could provide a novel potential approachfor treating human ovarian clear cell carcinoma.

To investigate expression of ILKAP among women with endometriosis and its association with clinical characteristics.A retrospective study was conducted at a center in China in 2012, using samples of ectopic (n=55) and eutopic (n=33) endometrium from women with endometriosis, and control endometrium samples (n=33) from women without endometriosis. Information on clinical characteristics was obtained from records. The expression of ILKAP was tested by immunohistochemistry.The expression of ILKAP was higher in the secretory phase of the menstrual cycle than in the proliferative phase, and it was lower in eutopic and ectopic endometriosis tissue than in control endometrium (P0.001 for both). A lower expression of ILKAP in ectopic endometrium was associated with moderate-to-severe dysmenorrhea, infertility for more than 1year, a cancer antigen 125 level of more than 35 U/mL, a disease duration of at least 1year, and American Fertility Society grade IV disease (P0.05 for all).A low level of ILKAP could facilitate the pathogenesis of endometriosis. Additionally, the level of ILKAP expression in ectopic endometrium might reflect the severity of endometriosis.

This study aims to analyze the risk of venous thromboembolism (VTE) in patients receiving neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC). A retrospective audit was conducted examining 147 patients treated for EOC. Surgical treatment with curative intent, with or without NACT and adjuvant chemotherapy, is the treatment approach, which was modified according to the patient's condition. The incidence of VTE with the most commonly used chemotherapy regimen, carboplatin, cisplatin, paclitaxel, docetaxel, and others were evaluated. This study found a 13.6% incidence of VTE in patients undergoing therapy with curative intent for EOC. No association was seen between NACT and VTE compared to VTE after standard treatment: 2/16 (12.5%) vs 5/131 (3.8%) (P = .16). Univariate and multivariate analyses also demonstrated that NACT has no risk for VTE with odds ratio (OR) = 0.89 (95% CI = 0.18–4.28) and P = 1. Results did not vary significantly with the type of chemotherapy used. Furthermore, increased incidence of VTE as an incidental finding supports the well-established role of malignancy in VTE occurrence. Univariate and multivariate analyses demonstrated that VTE occurred more frequently in menopausal women than nonmenopausal women (17.9% vs 5.8%) with OR = 3.55 (95% CI = 0.99–12.78) and P = .04 in patients aged ≥60 (19.3% vs 10%) with OR = 2.15 (95% CI = 0.83–5.57) and P = .13 but is not statistically significant. We conclude that NACT has no association with VTE and the currently used common chemotherapeutic drug combinations for ovarian cancer carry the minimal risk of thromboembolic events.

To first evaluate the predictive value of lymph-vascular space invasion (LVSI) and pelvic lymph node metastases (LNM) to parametrial invasion (PI) in patients with early stage cervical cancer. A systematic search of electronic databases was conducted to identify publications exploring the association between LVSI, LNM, and PI. The following databases were searched: PubMed/Medline and Web of Science. Twenty relevant studies were included. Pooling of results was done based on these studies and a diagnostic meta-analysis was performed. 20 articles and a total of 7373 cases were included in the meta-analysis. 17 studies analyzed the correlation between LVSI and PI and 18 studies evaluated the correlation between LNM and PI. The existence of LVSI accelerated PI with OR being 7.37 (95% CI 5.70–9.54) in fixed-effect model and 7.32 (95% CI 4.65–10.39) in random effects model. LVSI shows high sensitivity of 0.80 and the AUC was 0.82. The existence of LNM accelerated PI. LNM shows the highest specificity of 0.90 and the AUC was 0.77. Both LVSI and LNM are associated with PI. Conization and lymphadenectomy might be helpful to predict the parametrial status of patients with early stage cervical cancer. In addition, the results of this meta-analysis are helpful for designing further prospective clinical trials.

Long noncoding RNAs (lncRNAs) have recently emerged as pivotal regulators that govern fundamental biological processes and disease pathogenesis. LncRNA MNX1-AS1 has been reported to promote cell proliferation and invasion in gallbladder cancer, but its biological role and regulatory mechanism in ovarian cancer are poorly defined. In this study, it was found that higher expression of lncRNA MNX1-AS1 is closely associated with International Federation of Gynecology and Obstetrics stage and lymphatic metastasis in ovarian cancer patients. RNA interference (RNAi) to downregulate the expression of lncRNA MNX1-AS1 was used in the ovarian cancer cell lines, OVCA433 and SKOV-3. CCK-8, EdU staining, and colony formation assays was used to test the viability and proliferation ability of these cells. Wound healing and transwell migration assays were performed to determine the migration ability of the cells. Cell cycle progression and apoptotic assays were carried out using flow cytometry. These in vitro loss-of-function experiments revealed that downregulation of lncRNA MNX1-AS1 suppressed cell proliferation, colony formation, cell migration ability, induced cell cycle arrest at the G0/G1 phase, and promoted apoptosis. Furthermore, MNX1-AS1 knockdown altered the protein expressions of CDK4, cyclin D, Bax, and Bcl-2. These findings demonstrated for the first time that lncRNA MNX1-AS1 functions as an oncogene in ovarian cancer and could be a potential target for this disease.

Receptor tyrosine kinase–like orphan receptor 2 is an enzyme-linked receptor which specifically modulates WNT5A signaling and plays an important role in tumorigenesis, invasion, and metastasis; however, the precise role of receptor tyrosine kinase–like orphan receptor 2 in cancer is controversial. The purpose of this study was to investigate the expression and role of receptor tyrosine kinase–like orphan receptor 2 in ovarian carcinoma and clarify the biological functions and interactions of receptor tyrosine kinase–like orphan receptor 2 with non-canonical Wnt pathways in ovarian cancer. The result of the human ovary tissue microarray revealed that the receptor tyrosine kinase–like orphan receptor 2–positive rate increased in malignant epithelial ovarian cancers and was extremely higher in the metastatic tumor tissues, which was also higher than that in the malignant ovarian tumor tissues. In addition, high expression of receptor tyrosine kinase–like orphan receptor 2 was closely related with ovarian cancer grading. The expression of receptor tyrosine kinase–like orphan receptor 2 protein was higher in SKOV3 and A2780 cells than OVCAR3 and 3AO cells. Knockdown of receptor tyrosine kinase–like orphan receptor 2 inhibited ovarian cancer cell proliferation, migration, invasion, and induced morphologic as well as digestive state alterations in stably transfected SKOV3 cells. Detailed study further revealed that silencing of receptor tyrosine kinase–like orphan receptor 2 reversed the epithelial–mesenchymal transition and inhibited non-canonical Wnt signaling. Our findings suggest that receptor tyrosine kinase–like orphan receptor 2 may be an important regulator of epithelial–mesenchymal transition, primarily regulated the non-canonical Wnt signaling pathway in ovarian cancer cells, and may display a promising therapeutic target for ovarian cancer.

The systemic inflammatory response markers have been reported to be associated with the prognosis of various cancers. We conducted this meta-analysis of retrospective studies to evaluate and identify the prognostic impact of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on ovarian cancer. PubMed, EMBASE, and China National Knowledge Infrastructure databases were included to search for eligible studies. The following terms were used: “neutrophil to lymphocyte ratio”, “NLR”, “platelet to lymphocyte ratio”, “PLR”, “ovarian cancer”, “ovary cancer”, “ovarian carcinoma”, “ovary carcinoma”, “ovarian neoplasm”, “ovary neoplasm”, “ovarian tumor”, and “ovary tumor”. The random-effects model was chosen to estimate the pooled HR with 95% CI. Heterogeneity between studies was assessed by Higgins I2 value. The stability and heterogeneity of studies were analyzed by sensitivity analysis. Publication bias was examined by Egger’s test and Begg’s test with the funnel plots. 13 studies consisting of 3467 patients were considered for meta-analysis. We found that the high NLR had a poor prognostic impact on OS and PFS in ovarian cancer, with a pooled HR 1.70, 95% CI 1.35–2.15 and HR 1.77, 95% CI 1.48–2.12, respectively. Similarly, the results showed the high PLR adversely affected OS and PFS in ovarian cancer, with a pooled HR 2.05, 95% CI 1.70–2.48 and HR 1.85, 95% CI 1.53–2.25, respectively. In conclusion, we found that both NLR and PLR had an unfavorable impact on PFS and OS of patients with ovarian cancer. Our meta-analysis supported that NLR/PLR could be effective prognostic predictors of ovarian cancer.

Introduction: The presence of subset of cancer stem cells (CSCs) called “Side population” (SP) cells has been identified in several solid tumors, responsible for treatment failure especially chemotherapy, and cancer relapse. The present study was aimed to isolate and characterize cancer stem like cells side population cells from high grade ovarian cancer. Methods: The collected cancer samples were analyzed for presence of SP cells by FACS using Hoechst 33342 exclusion technique. Further the FACS sorted SP and non-SP cells were subjected to analysis of stem cell surface protein expression by western blot and immunocytochemistry, drug resistance and sphere formation assay. Results: By FACS, we have identified 3.7% of cancer stem cell like side population cells in ovarian cancer whose prevalence was reduced to 0.5% upon treatment with verapamil an inhibitor of ABC transporter. Further, these sorted SP cells showed over expression of ABCG2 (ABC transporter), stem cell proteins such as CD144, CD44, EpCAM and antiapoptotic factor Bcl-2. Also the SP cells showed high resistance to chemotherapy drugs, have high survival rate and they are highly potential to form tumor spheres. Conclusion: Our data suggest that ovarian cancer contain small sub-population of side population cells which shares some characteristics of stem cells. The co-expression of ABC transporters and stem cells surface markers in SP cells may associate with resistance to chemotherapeutic agents, apoptosis and also supports a role for these cells in tumor recurrence, metastasis and invasion.

The purpose of our study was to investigate the therapeutic potential of Celecoxib for epithelial ovarian cancer, especially on cellular morphological changes, proliferation invasion and epithelial-mesenchymal transition (EMT). The MTT and transwell assays were performed to evaluate the effect of Celecoxib on proliferation and invasion ability of ovarian cancer cell lines, respectively. Western blot was carried out to detect the expression of epithelial phenotypes, E-cadherin and Keratin, and mesenchymal phenotypes, N-cadherin and Vimentin, as well as p-AKT, p-ERK and ZEB1. ZEB1 small-interfering RNA (siRNA) was used to downregulate the expression of ZEB1 to further inquiring into the downstream of Celecoxib-induced EMT. Cellular morphological assessment revealed that both A2780 and SKOV3 cells gradually appeared in the morphology of mesenchymal cells after Celecoxib treatment. The MTT assay demonstrated that celecoxib had no effect on cell proliferation. Transwell assay showed that Celecoxib significantly increased the cell invasion ability. Western blot data proved that the expression of E-cadherin and keratin was elevated, whereas the expression of N-cadherin and Vimentin was decreased in a dose-dependent manner compared with the untreated cells, the expression of p-AKT, p-ERK and ZEB1 was also obviously elevated. However, ZEB1 siRNA reversed Celecoxib-induced E-cadherin expression and N-cadherin expression, as well as cellular invasiveness. Our results indicated that Celecoxib might induce EMT and increase cellular invasiveness in ovarian cancer cells in vitro, which also implied that it needed a comprehensive evaluation in preclinical researches before introducing Celecoxib into the clinical regimen.

Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis, through which cancer cells acquire an invasion and metastasis capacity. Notably, the chemokine receptor CXCR7 and its ligands CCL19 can also facilitate lymph node metastasis in epithelial ovarian carcinomas. Here, we assumed that CXCR7 might be involved in the EMT process of epithelial ovarian carcinomas. In our study, CXCR7 activation and inhibition in SKOV3 were induced with exogenous CCL19 and CXCR7 small interfering RNA (CXCR7 siRNA), respectively. AKT and ERK protein of CXCR7 pathways as well as biomarkers (vimentin, snail, N-cadherin, and E-cadherin) of EMT were detected using the Western blot. Our results showed that CCL19 can induce AKT and ERK phosphorylation in a dose-dependent fashion; however, CXCR7 siRNA efficaciously suppressed CCL19-induced AKT and ERK phosphorylation in comparison with control siRNA. Importantly, CCL19 alone treatment can upregulate the expression of vimentin, snail, and N-cadherin of SKOV3 and downregulate the expression of E-cadherin. Conversely, knockdown of CXCR7 did not reveal any changes compared with CCL19 and the control. In conclusion, these findings demonstrate that EMT can be regulated by the CCL19/CXCR7 axis in epithelial ovarian carcinomas and then involved in the tumor cell invasion and metastasis process via activation of AKT and ERK pathways. Our study lays a new foundation for the treatment of epithelial ovarian carcinomas through antagonizing CXCR7.

Rationale Primary melanomas of the female genital tract are rare and usually occur in the vulva and vagina. Involvement of the cervix, uterus, and ovary are extremely rare. Surgery and adjuvant therapy remain the mainstay of treatment. The majority of patients experience poor long-term survival. This report aimed at highlighting an extremely rare case of primary melanoma of the female genitalia, synchronously involving the vulva and uterine cervix. Patient concerns A 58-year-old multiparous female presented with postmenopausal bleeding for 10 days. Diagnoses Speculum examination and histologic analysis of the surgical specimens revealed synchronous involvement of the vulva and uterine cervix by malignant melanoma. According to the American Joint Committee on Cancer stage grouping for melanoma, this tumor was at stage V. Interventions The patient subsequently underwent radical surgery and postoperative chemotherapy. Outcomes She has been on regular follow-up, and is now free of disease for 50 months after the operation. Lessons Primary melanomas of the female genital tract have biologically aggressive characteristics. Optimal management consists of individualized surgery and adjuvant therapy. However, early recognition and prompt intervention offer maximal benefit from treatment.

The signal transducer and activator of transcription 3 (STAT3) regulates target gene expression by binding to a consensus DNA sequence within the promoter of the target genes. The constitutive activation of STAT3 has been shown to contribute to tumorigenesis in ovarian cancer and it has been reported to be a key factor for drug resistance in ovarian cancer. STAT3-specific decoy oligodeoxynucleotides (ODNs) (STAT3 decoy ODNs) that contain a consensus DNA sequence inhibit the transcriptional activity of STAT3, leading to cancer cell death. However, their mechanisms of action are unclear and little information is available as to the effects and the toxicity of STAT3 decoy ODNs in vivo. In this study, we established subcutaneous xenografts of SKOV3 human ovarian cancer cells in nude mice, evaluated the antitumor effects of STAT3 decoy ODNs on xenografted nude mice, and investigated the mechanisms behind the antitumor effects of STAT3 decoy ODNs targeting the STAT3 signaling pathway in vivo. The results revealed that the STAT3 decoy ODN inhibited ovarian cancer cell growth and promoted ovarian cancer cell apoptosis in vivo. Western blot analysis indicated that the STAT3 decoy ODN downregulated the protein expression levels of matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2, and upregulated the protein expression levels of caspase-3 in vivo. H&E staining was used to detect the side-effects of the STAT3 decoy ODN in the vital organs of the nude mice. We found that there were no significant abnormalities in the vital organs of the nude mice apart from slight inflammation and necrosis in parts of the hepatic lobule. The data from the present study suggest that decoy ODNs targeting STAT3 may be an effective therapeutic approach for the treatment of ovarian cancer in vivo.

Introduction Autophagy has been reported to play important roles in tumorigenesis. This meta-analysis was conducted in order to investigate the association between autophagy-related proteins, beclin 1 and LC3, with prognostic value and clinical characteristics of ovarian cancer. Evidence acquisition PubMed, EMBASE and CNKI databases (up to August 2016) were searched for eligible studies using the following key words: "beclin 1", "beclin-1", "Becn 1", "Becn-1", "Atg6", "LC3", "ovarian cancer", "ovarian carcinoma", "ovarian neoplasm", "ovarian tumor", "ovary cancer", "ovary carcinoma", "ovary neoplasm", "ovary tumor". The random effects model was used to combine effect sizes. Higgins I2 value was used to examine heterogeneity between studies. Sensitivity analysis was used to investigate the heterogeneity and the stability of the results. Egger's test and Harbord's test were used to examine publication bias. Evidence synthesis Eight studies including a total of 872 patients were eligible for this meta-analysis. The results showed expressions of both beclin 1 (OR=0.498, 95% CI: 0.298-0.832) and LC3 (OR=0.308, 95% CI: 0.142-0.668) were associated with FIGO stage (FIGO I/II versus FIGO III/IV). However, no association was found between the expression of beclin 1 and overall survival (HR=0.678, 95% CI: 0.434-1.058), age (OR=0.965, 95% CI: 0.473-1.967), lymph node metastasis (OR=0.517, 95% CI: 0.218-1.227), pathological classification (OR=0.895, 95% CI: 0.649-1.233) and differentiation (OR=0.571, 95% CI: 0.261-1.247). Similarly, no relationship was found between LC3 with age (OR=0.947, 95% CI: 0.399-2.248), pathological classification (OR=0.821, 95% CI: 0.410-1.644), and differentiation (OR=0.432, 95% CI: 0.118-1.580). Conclusions Autophagy-related proteins might be important markers of ovarian cancer progression. However, due to the limited number of original studies, more well-designed, large-scale, high-quality studies are needed, which provide new, valuable information for further investigation.

Ovarian cancer is the most lethal gynecologic malignancy worldwide with surgery as the only curative treatment. Long-term overall survival (OS) of ovarian cancer is far from satisfactory, even though significant improvement has been made in post-operative chemotherapy. One of the most important death cause is the chemoresistance due to consecutive chemotherapy. Therefore, understanding the molecular mechanisms involved in ovarian cancer development and identification of novel therapeutic targets are urgently required. Immunohistochemical (IHC) staining was used to explore the expression pattern of mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) in tumor tissues from 138 epithelial ovarian cancer (EOC) patients. Clinicopathological data were subjected to Kaplan–Meier survival and Cox multivariate analyses to evaluate the prognostic value of MNK1 in EOC. Overexpression and silencing procedures were performed on OVCAR-5 cells to investigate the mechanisms of MNK1 in regulating EOC development. The anti-tumor effects of CGP57380, a specific MNK inhibitor, were examined by cell viability assay. Higher MNK1 expression showed significant relationship with advanced FIGO stage and positive lymph node metastasis of EOC. Univariate and multivariate analyses revealed that MNK1 was an independent prognostic factor for OS of EOC patients. In vitro study demonstrated that MNK1 can promote cell proliferation through regulating the phosphorylation level of eukaryotic initiation factor 4E. In addition, inhibition of MNK1 by CGP57380 significantly down-regulated the OVCAR-5 cell viability. High MNK1 expression in EOC tissues indicates poor clinical outcomes, and MNK1 can act as a potential target for novel chemotherapy development towards EOC.

XIAP-associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that can reverse the anti-apoptotic effect of XIAP. XAF1 levels are greatly decreased in many cancer tissues and cell lines. The aim of this study was to investigate the expression of XAF1 and XIAP in advanced epithelial ovarian cancer and role of XAF1 in cisplatin resistance of ovarian cancer cells. Tissues from 94 patients with advanced epithelial ovarian cancer (EOC) and 30 ovarian cystadenomas were obtained. We analyzed the association of the immunohistochemical-determined expression of these two factors and clinicopathologic variables, overall survival, and angiogenesis. We established SKOV3 cells stably overexpressing XAF1 and explored the possible functions of XAF1 in ovarian cancer cells in vitro and in vivo. The protein expression of XAF1 was significantly lower and that of XIAP higher in malignant than nonmalignant tissues. Low XAF1 expression was associated with high-grade tumors and poor overall survival for patients. XAF1 expression was associated with microvessel density. Overexpression of XAF1 suppressed cell proliferation and enhanced SKOV3 cells sensitivity to cisplatin, as well as inhibited tumor growth and decreased MVD in vivo. Overexpression of XAF1 induced XIAP inactivation, caspase-3 activation and cytosolic expression of cytochrome c. These results suggested that XAF1 may be involved in ovarian cancer development and up-regulation of XAF1 may confer sensitivity of ovarian cancer cells to cisplatin-mediated apoptosis.

To investigate the expression of periostin in the eutopic and ectopic endometrium of women diagnosed as endometriosis and evaluate the role of periostin in the pathogenesis of endometriosis.In this study, the expression of periostin was evaluated in the endometrial specimens from 35 women diagnosed as endometriosis and from 30 healthy women. To assess the presence and localization of periostin throughout the menstrual cycle in both eutopic and ectopic endometrium of women with endometriosis, microscopic evaluation was conducted. It was also subsequently compared with normal endometrium.In the eutopic and ectopic endometrium of women with endometriosis, immunoreactivities of periostin increased compared with those of normal endometrium. We also observed a cyclic variation in the eutopic stromal periostin immunoreactivity throughout their menstrual cycle because higher H score values were observed in the proliferative phase than those in the secretory phase.These findings indicated that periostin may be involved in the pathophysiology of endometriosis.

HO-1 has been proved to be associated with tumor aggressivity and poor prognosis in various cancers. Our study provides the first study to demonstrate the relationship of HO-1 expression and clinical characteristics in ovarian cancer patients. Immunohistochemistry and western blotting were used to examine the expression of HO-1 in tissue species and fresh tissues. CCK-8 was used to investigate cell viability. Transwell chamber was performed to estimate migration and invasion capacities in A2780 and Skov-3 cells. Immunohistochemistry and western blotting showed that the expression of HO-1 was higher in ovarian cancer tissues than normal ovarian tissues. High expression of HO-1 was significantly associated with serous ovarian cancer, high FIGO stage, lymph node metastasis, and non-optimal debulking. Patients with high expression of HO-1 exhibited an unfavorable prognosis. In vitro inducing the expression of HO-1 promoted the proliferation and metastasis of A2780 and Skov-3 cells, with the increased expressions of mesenchymal marker (Vimentin), epithelial–mesenchymal transition-associated transcript factor (Zeb-1), anti-apoptotic protein (Bcl-2), and the decreased expressions of epithelial marker (Keratin) and pro-apoptotic protein (Bax). Meanwhile, after incubating A2780 and Skov-3 together with HO-1 inhibitor, above results could be reversed. HO-1 might be a potential marker for prediction of ovarian cancer prognosis and a target for ovarian cancer treatment.

Papillary differentiation is one of the most common histological features of ovarian cancer, although the underlying mechanism that leads to such differentiation is not known. We hypothesized that human ovarian surface epithelial cells can be transformed into carcinoma with papillary differentiation by overexpressing HER2/neu in these cells. Mice were injected either subcutaneously or intraperitoneally with two immortalized human ovarian surface epithelial cell lines after enforced expression of HER-2/neu. Mice subcutaneously injected with tumor cells from either the T29Nt or T80Nt developed undifferentiated carcinomas. In contrast, mice injected intraperitoneally with T29Nt cells developed papillary carcinoma, and those injected intraperitoneally with T80Nt cells developed undifferentiated carcinoma. Our results demonstrate that ovarian surface epithelial cells can develop into papillary carcinoma in mice, and that the induction of papillary differentiation depends not only on specific genetic modifications but also on the tumor microenvironment and epithelial cell type from ovary from different patients.

To investigate whether postoperative GnRH agonist (GnRH-a) treatment can prevent endometriosis recurrence. This meta-analysis searched PubMed, Embase and Cochrane Library for relevant studies published online before June 2015. Seven randomized controlled trials including 328 patients with postoperative GnRH-a treatment and 394 patients in control group were included in the meta-analysis. In the meta-analysis, the recurrence rate of GnRH-a group compared with control group was evaluated with odds ratio (OR) and its 95 % confidence interval (CI). Heterogeneity, small study effect and publication bias were, respectively, assessed using Higgins I 2, sensitivity analysis and funnel plot. Postoperative GnRH-a treatment for endometriosis (pooled OR = 0.71; 95 % CI 0.52–0.96) was superior to expectant or placebo treatment in prevention of the recurrence. The recurrence rate decreased significantly in patients who received 6 months GnRH-a treatment (pooled OR = 0.59, 95 % CI 0.38–0.90), whereas no significant difference of recurrence rate existed between patients with 3 months post-surgical GnRH-a therapy and the control group (pooled OR = 0.87, 95 % CI 0.56–1.34). No significant heterogeneity and small study effect were found in the meta-analysis. However, publication bias did existed in the present meta-analysis. Longer-term (6 months) postoperative administration of GnRH-a can decrease the recurrence risk of endometriosis, whereas 3 months duration of GnRH-a therapy makes no significant difference in preventing the recurrence of endometriosis. Therefore, instead of a 3 month therapy, the duration of the postoperative administration should be longer enough (6 months) to prevent the recurrence of endometriosis.

Background Endometrial polyps (EP) and endometriosis are both estrogen-dependent overgrowths of the endometrium. Several studies have shown a higher frequency of EP in endometriosis patients when compared with women without endometriosis. Therefore, we performed a meta-analysis to investigate the risk of EP in women with endometriosis. Methods This meta-analysis searched for articles published between 1964 and 2014 in PubMed, Embase, and Cochrane Library, as well as in Chinese databases, including CNKI, VIP and Wanfang, regarding the association between endometriosis and EP. Nine cohort studies and one case–control study including 2896 women were included in this meta-analysis. The EP risk was evaluated using relative risk (RR) with a 95 % confidence interval (CI). Heterogeneity, small study effect and publication bias were assessed using Higgins I2, sensitivity analysis and funnel plots, respectively. Results The risk of EP increased in women with endometriosis compared with those without endometriosis (the pooled RR, 2.81; 95 % CI, 2.48–3.18). No significant heterogeneity, small study effect or publication bias was found. The risk of EP slightly increased in women with endometriosis at stages 2–4 compared with those at stage 1 (Pooled effect size: stage 2 versus stage 1, RR, 1.22, 95 % CI, 1.04 - 1.42; stage 3 versus stage 1, RR, 1.23, 95 % CI, 1.06–1.42; stage 4 versus stage 1, RR, 1.29, 95 % CI, 1.11–1.51; stages 2–4 versus stage 1, RR, 1.24, 95 % CI, 1.10–1.40); however, no significantly different risk of EP in women with endometriosis existed between the other stages. Conclusion The results suggest that it is important to identify whether patients with endometriosis also have EP and then remove any coexisting EP via hysteroscopy, especially for infertile patients. This process will be clinically helpful to treat endometriosis-related infertility in patients with endometriosis, especially for those with endometriosis that is more serious than stage 1. Electronic supplementary material The online version of this article (doi:10.1186/s12958-015-0092-2) contains supplementary material, which is available to authorized users.

Objective: To analyze the clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. Methods: One hundred and eight tissue samples from the patients with endometrial cancer enrolled in our hospital from August 2011 to July 2014 were selected, including 60 normal tissue samples (normal group), 60 neoplastic tissue samples (neoplastic group) and 60 cancer tissue samples (cancer group). All the samples were subjected to immunohistochemical assay to detect the expressions of COX-2, GLUT-1 and VEGF. The clinical data were also investigated for correlation analysis. Results: The positive rates of COX-2 in normal group, neoplastic group and cancer groups were 3.3%, 21.7% and 55.0% respectively. The positive rates of GLUT-1 in normal group, neoplastic group and cancer groups were 3.3%, 25.0% and 70.0% respectively. The positive rates of VEGF in normal group, neoplastic group and cancer groups were 1.7%, 23.3% and 63.3% respectively. With increasing stage of such cancer, decreasing degree of differentiation and lymphatic metastasis, the positive expression rates of COX-2, GLUT-1 and VEGF proteins were raised significantly (P

Markers associated with diagnosis, presentation and potential therapeutic targets have received widespread attention in ovarian cancer research in the past few years. However, the majority of these markers have been investigated individually, and the changes in expression and the association between them are rarely documented. Next‑generation sequencing, also termed RNA-seq when the sequencing targets are cDNAs, can provide a whole blueprint of the transcriptome of a specific tissue. In the present study, RNA-seq data of human ovarian cancer samples were used to verify the expression of known markers and to identify the association between them. A total of 563 markers associated with ovarian cancer were retrieved from the database of the National Center of Biotechnology Information, and used as the target markers. The transcriptome of the ovarian tissue of four different tumors, containing tumor presentation and recurrence stages, were sequenced using the Illumina GAII platform. Approximately 85.97% markers were expressed of the total 563 markers, and the majority of them were involved in pathways associated with cancer, signaling and infection. In total, 85 markers were found to be aberrantly expressed in tumor cells from patients with ovarian cancer who had recurrences, including 33 upregulated markers at the recurrence stage. Therefore, they may have roles ovarian tumor due to their aberrant expression. Differentially expressed markers and the associations between them can be assessed by examining the RNA-seq data. These findings may provide novel information for further studies on ovarian cancer.

To investigate a better approach for androgen insensitivity syndrome (AIS) treatment using laparoscopic peritoneal or ileal vaginoplasty. Improved laparoscopic peritoneal vaginoplasty and gasless laparoscopic ileal vaginoplasty were, respectively, applied to AIS patients in vaginal reconstruction. The operation condition and surgical results were summarized and follow-up was performed from the 5th week after operation, then once a month. The sexual function was scored by Female Sexual Function Index (FSFI), and FSFI score >30 represented a very good sexual function, 25–30 as good, and

Though many studies were published to assess the relationship between p21 Ser31Arg polymorphism and cervical cancer, there was no definite conclusion on this association. To provide a quantitative assessment of the relationship between p21 Ser31Arg polymorphism and cervical cancer, we performed a meta-analysis of 10 eligible studies (1,539 cases and 2,161 controls). All those 10 studies were from Asians. The odds ratios (OR) with 95 % confidence intervals (95 %CIs) were used to assess the strength of the association, and the pooled ORs were calculated for the codominant model (ArgArg vs. SerSer), the dominant model (ArgArg/SerArg vs. SerSer), and the recessive model (ArgArg vs. SerSer/SerArg). Meta-analysis of those 10 studies showed that there was no association between p21 Ser31Arg polymorphism and cervical cancer risk in Asians under all three models (ArgArg vs. SerSer: OR = 1.04, 95 %CI 0.66–1.65, P = 0.86, I 2 = 78 %; ArgArg/SerArg vs. SerSer: OR = 0.93, 95 %CI 0.66–1.30, P = 0.66, I 2 = 81 %; ArgArg vs. SerSer/SerArg: OR = 1.20, 95 %CI 0.84–1.73, P = 0.32, I 2 = 72 %). Sensitivity analysis performed by omitting each study in turn showed that the pooled results were stable. In summary, there is no association between p21 Ser31Arg polymorphism and cervical cancer risk in Asians. Further studies are needed to assess the possible association between p21 Ser31Arg polymorphism and cervical cancer risk in Caucasians.

It is uncommon that fertility is preserved in young nulliparous females with low-grade endometrial stromal sarcoma (ESS). Therefore, successful pregnancy following such conservative management has been rarely reported in previous literature. A 25-year-old female (gravida, 0; para, 0) underwent hysteroscopic surgery and was pathologically diagnosed with an endometrial stromal nodule. The patient underwent fertility-preserving local resection and uterine reconstruction, with a final pathological diagnosis of low-grade ESS. Endocrine therapy was then administered. Conservative management resulted in the complete remission of low-grade ESS. The patient naturally conceived and successfully delivered a healthy baby at 42 weeks' gestation by cesarean section, ~30 months following diagnosis with low-grade ESS. In conclusion, conservative management, including fertility-preserving local mass resection and endocrine therapy, can be effective for low-grade ESS and may yield a favorable outcome for young nulliparous females desiring fertility preservation.

The aim of this study was to investigate the expression of Runt box 3 (RUNX3) and aplasia Ras homolog member I (ARHI) in ovarian tumors, and the effects of histone deacetylase inhibitors (HDACIs) on the expression of these genes and the growth of ovarian cancer cells. The mRNA expression of the RUNX3 and ARHI genes in normal ovaries and ovarian tumors was determined using reverse transcription polymerase chain reaction (RT-PCR). The effects of HDACIs on RUNX3 and ARHI expression in four ovarian cancer cell lines (SKOV3, A2780, COC1 and OC3) were determined using RT-PCR and the MTT assay. The expression of RUNX3 and ARHI in normal ovarian cells was 86 and 100%, respectively. Although the two genes were downregulated in ovarian tumors, the extent of downregulation differed. The expression of RUNX3 and ARHI was correlated with the degree of tumor malignancy (P

Altered metabolism is one of the most significant features of cancer cells. ATP citrate lyase (ACL), a key enzyme in de novo lipid synthesis, has been reported to be overexpressed or activated in several cancer types. To determine the role of ACL in ovarian cancer progression, we detected ACL expression in human epithelial ovarian cancer tissues. qRT-PCR and western blotting showed higher ACL expression in malignant tissues compared to normal ovarian tissues. Immunohistochemical analysis showed that phosphorylated ACL was increased in ovarian cancer tissues and that its expression correlated well with tumor grade, FIGO stage and poorer prognosis. To explore the therapeutic potential of ACL, we assessed the effect of ACL-siRNA on cellular proliferation and cell cycle distribution. ACL knockdown inhibited cellular proliferation and induced cell cycle arrest in A2780 cells. Taken together, our findings suggest that ACL may contribute to the pathogenesis of human epithelial ovarian cancer, and may serve as a novel therapeutic target.

Purpose: As a member of the p53 family, p63 is considered to be an important differentiation regulation transcriptional factor, but the roles of p63 in many epithelial tumourigenesis and metastasis processes are still not clear. This study was designed to investigate the expression of p63 and its isoform in normal tissues and squamous cell cancer tissues of uterine cervix, and its significance in cancer cell differentiation. Methods: The expression of p63 was assessed in cervical tissue and cell lines by immunohistochemistry, RT-PCR and Western Blotting. The relationships between p63 protein, various clinico-pathological features, and the differentiation marker involucrin were analyzed. Results: ΔΝp63α is the predominant isoform expressed in cervical epithelial tissues, and it is decreased in moderately or poorly differentiated cervical squamous carcinoma, as well as in the HeLa, SiHa and C33A cervical cancer cell lines. The expression level of ΔΝp63α was positively correlated with that of involucrin in cervical squamous cancer tissue, and the expression of ΔΝp63α is decreased with the degree of tumour invasion. Conclusion: The decrease of ΔΝp63α in cervical squamous cell cancer appears to be associated with the tumour progression, and ΔΝp63α may be a sensitive marker for cervical squamous cancer differentiation.

Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world, and the development of drug resistance is a major impediment toward successful treatment of the desease. Emodin has been reported to sensitize human tumor cells to chemotherapeutic agents. The present study investigated whether emodin could overcome chemoresistance of A2780/taxol cells. Cells were treated with different concentration of emodin alone or combined with paclitaxel, then the cell viability was measured by MTT and the apoptosis was determined by flow cytometric analysis. The changes of mRNA and protein were examined by QRT-PCR and Western blotting. The function of P-glycoprotein was also determined by flow cytometry. The results showed that emodin induced apoptosis alone at a high concentration and increased paclitaxel-induced apoptosis at a low concentration. It enhanced the sensitivity of A2780/taxol cells to paclitaxel with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, the results demonstrated a dual role for emodin in the inhibition of drug resistant ovarian tumor growth by increasing paclitaxel cellular concentration and re-sensitizing the resistant cells to paclitaxel. Our results suggest the possibility of an innovative chemotherapeutic strategy that uses emodin in combination with paclitaxel to increase the sensitivity of tumor cells.

Cornification is a kind of apoptosis of squamous epithelial cell in the upper layer of the epithelial tissue. The basal cells away from cell-cycle embark on terminal differentiation, stratum, then die by apoptosis. The critical elements interference from the normal differentiation of squamous cells will lead to cell malignant transformation. We would like to put forward a hypothesis that initiation the cornification of squamous cancerous cells by promotion cell differentiation and stratum can promote squamous carcinoma cells death. Attempts of induction squamous cancerous cells terminal differentiation will add to our understanding of the connection between keratinocytes cornification and the death of squamous-cell carcinoma.