LncRNA IDH1-AS1 sponges miR-518c-5p to suppress proliferation of epithelial ovarian cancer cell by targeting RMB47

Long noncoding RNA(lncRNA)IDH1 antisense RNA 1(IDH1-AS1)is involved in the progression of multiple cancers,but its role in epithelial ovarian cancer(EOC)is unknown.Therefore,we investigated the expression levels of IDH1-AS1 in EOC cells and normal ovarian epithelial cells by quantitative real-time PCR(qPCR).We first evaluated the effects of IDH1-AS1 on the proliferation,migration,and invasion of EOC cells through cell counting kit-8,colony formation,EdU,transwell,wound-healing,and xenograft assays.We then explored the downstream targets of IDH1-AS1 and verified the results by a dual-luciferase reporter,qPCR,rescue experiments,and Western blotting.We found that the expression levels of IDH1-AS1 were lower in EOC cells than in normal ovarian epithelial cells.High IDH1-AS1 expression of EOC patients from the Gene Expression Profiling Interactive Analysis database indicated a favorable prognosis,because IDH1-AS1 inhibited cell proliferation and xenograft tumor growth of EOC.IDH1-AS1 sponged miR-518c-5p whose overexpression promoted EOC cell proliferation.The miR-518c-5p mimic also reversed the proliferation-inhibiting effect induced by IDH1-AS1 overexpression.Furthermore,we found that RNA binding motif protein 47(RBM47)was the downstream target of miR-518c-5p,that upregulation of RBM47 inhibited EOC cell proliferation,and that RBM47 overexpressing plasmid counteracted the proliferation-promoting effect caused by the IDH1-AS1 knockdown.Taken together,IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.

PHASE Ⅱ STUDY OF GEMCITABINE COMBINED WITH PLATINUM CHEMOTHERAPY FOR RECURRENT EPITHELIAL OVARIAN CANCER

Objective To evaluate the anti-tumor effect and toxicity of gemcitabine combined with platinum chemotherapy on recurrent epithelial ovarian cancer. Methods Phase Ⅱ study of gemcitabine combined with platinum chemotherapy was carried out in 22 patients with recurrent epithelial ovarian cancer. Median age of patients was 50. 5 years old. Seven patients were platinum-sensitive and 15 patients were platinum-resistant or -refractory. All patients received gemcitabine combined with carboplatin or oxa/iplatin chemotherapy. Patients＇ response rate （RR） and toxicity of gemcitabine combined with platinum chemotherapy were evaluated. Results A total of 98 gemcitabine-based chemotherapy cycles were performed. Total RR was 36. 4%, RR of platinum-sensitive patients was 4/7 and platinum-resistant and -refractory patients was 4/15. The estimated median survival time was 10.0 months （95% CI. 7.0-13.0） after initiation of gemcitabine combined with platinum chemotherapy. There was no significant difference in survival time between platinum-resistant/refractory group and platinum-sensitive group （P = 0. 061 ）. Side effects of gemcitabine combined with platinum chemotherapy were observed in 81.8% of patients. Grade Ⅱ/Ⅲ anemia （54. 5% ） and grade Ⅲ/Ⅳ neutropenia （54. 5% ） were most common toxicities. Ten （45.5%） patients had to delay their chemotherapy cycles or reduce the dose of chemotherapeutic drugs because of the severe side effects. Fourteen （63.6%） patients received granulocyte colony-stimulating factor to relieve neutropenia, and 8 （ 36. 4% ） patients received component blood transfusion to treat anemia or thrombocytopenia. There was no treatment-associated death. Conclusion Gemcitabine combined with platinum chemotherapy appears to be an effective and well-tolerant treatment for recurrent epithelial ovarian cancer, including platinum-resistant or -refractory diseases.

Unlocking the future:Mitochondrial genes and neural networks in predicting ovarian cancer prognosis and immunotherapy response

BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.

Recurrent epithelial ovarian cancer and hormone therapy

The role of hormone therapy in the treatment of ovarian cancer is not clear. Data on the efficacy and safety of antiestrogens and aromatase inhibitors in recurrent ovarian cancer have been accumulated through phase Ⅱ clinical studies. Most of these studies were conducted in platinum-resistant recurrent ovarian cancer, and although complete response rates were not high, reported adverse events were low. If administered to patients who are positive for estrogen receptors, hormone therapy may become a viable option for the treatment of recurrent ovarian cancer.

Pegylated Liposomal Doxorubicin as a Single Agent or as Combination Therapy with Carboplatin in Patients with Recurrent or Refractory Epithelial Ovarian Cancer

OBJECTIVE Pegylated liposomal doxorubicin （PLD; CAELYX ）, a novel formulation of doxorubicin with enhanced therapeutic efficacy and reduced toxicity, has demonstrated improved progression-free survival in recurrent or refractory ovarian cancer. The objective of this open-label, noncomparative, observational study was to determine the efficacy and safety of PLD monotherapy or combination therapy with carboplatin for patients with cancer. recurrent or refractory ovarian METHODS Sixty-two patients with recurrent or refractory ovarian cancer who completed a platinum-based chemotherapy regimen and demonstrated platinum sensitivity for first-line treatment at least 6 months prior to study entry were enrolled in 20 centers in China. PLD was given as monotherapy （50 mg/m2 infused over 60 minutes） or as combination therapy （30 mg/m2 1-hour infusion） with carboplatin （area under the curve 5 mg.min/mL 1-hour infusion） on day 1 every 28 days for 4 cycles. The primary endpoint was objective response （OR） rate or CA-125 level. Secondary endpoints included time to response, time-to-progression, health-related quality of life, and safety. RESULTS Overall, 48% of the 62 evaluable patients achieved a confirmed OR. More patients receiving PLD and carboplatin achieved an OR vs the PLD monotherapy group （63% vs. 37%）. The median time to response and disease progression was 58.5 days and 56.0 days, respectively. Overall and drug-related adverse events were reported for 39% and 34%, respectively. The most commonly reported adverse events were stomatitis （22.6%） and palmar-plantar erythroderma （9.7%）. Two deaths were reported. CONCLUSION PLD is an effective and well tolerated agent in women with recurrent or refractory epithelial ovarian cancer.

A Pilot Study of Gemcitabine and Epirubicin Combination Chemotherapy as a Salvage Regimen for Recurrent Platinum Resistant and/or Refractory Epithelial Ovarian Cancer

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the antitumor activity and toxicity profile of gemcitabine combined with epirubicin in patients with recurrent platinum refractory ovarian epithelial cancer. PATIENTS AND METHODS: Patients with recurrent platinum refractory ovarian cancer and with adequate hematologic, renal and hepatic function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 were enrolled. The regimen was Gemcitabine 1000 mg/m2 (day 1, 8) and Epirubicin 60 mg/m2 (day 1), the cycle was repeated at interval of 21 days. RESULTS: Twenty eight patients were recruited and received 156 cycles of gemcitabine-epirubicin combination chemotherapy (median 6 cycles). Overall response rate was 42.9% (95% CI equal 24.5 to 62.7) and tumor control rate was 75% (95% CI equal 55.1 to 89.3). No complete responses were observed. Median progression-free and median overall survival times were 7 and 15 months, respectively. The most common grade 3/4 hematological toxicities were neutropenia (57.1%), anemia (10.7%), and thrombocytopenia (7.1%), while the most common grade 3/4 non-hematological toxicities were mucositis (14.3%) and vomiting (3.6%). No treatment related deaths were observed. CONCLUSION: Gemcitabine combined with epirubicin regimen appeared to offer an acceptable clinical profile in patients with recurrent platinum-refractory epithelial ovarian cancer.

Cytoreductive surgery after recurrent epithelial ovarian cancer and at other timepoints

In this descriptive review we look at the role of surgery for advanced ovarian cancer at other timepoints apart from the initial cytoreduction for front-line therapy or interval cytoreductive surgery after neoadjuvant chemotherapy. The chief surgical problem to face after primary treatment is recurrent ovarian cancer. Of far more marginal concern are the second-look surgical procedures or the palliative efforts intended to resolve the patient's symptoms with no curative intent. The role of surgery in recurrent ovarian cancer remains poorly defi ned. Current data, albeit from non-randomized studies, nevertheless clearly support surgical cytoreduction in selected patients, a rarely curative expedient that invariably yields a marked survival advantage over chemotherapy alone. Despite these fi ndings, some consider it too early to adopt secondary cytoreduction as the standard care for patients with recurrent ovarian cancer and a randomized study is needed. Two ongoing randomized trials(Arbeitsgemeinschaft Gynkologische Onkologie-Desktop Ⅲ and Gynecologic Oncology Group 213) intend to verify the role of secondary cytoreduction for platinum-sensitive ovarian cancer compared with chemotherapy considered as standard care for these patients. We await the results of these two trials for a defi nitive answer to the matter.

Expression and clinicopathologic significance of RASSF1A and WT1 in recurrent epithelial ovarian cancer

Objective To explore the expression and clinicopathological significance of RASSF1A and WT1 in recurrent epithelial ovarian cancer.Methods Sixty-three cases of patients with pathologically confirmed epithelial ovarian cancer were collected in the department of Gynaecology and Obsterics of the North China University of Technology from January 2013 to December 2018.The expression of RASSF1A and WT1 were measured by IHC staining.The relation of these proteins with ovarian cancer was also analyzed.Results Compared with non-recurrent group(46.4%),the positive expression rate of RASSF1A was 17.1%in recurrent group.The positive expression rate of WT1 was 74.3%and higher than the rate of 42.8%in non-recurrent group.The reducing expression of RASSF1A was related to clinical stage,differentiation,and with ascites(P<0.05).The increasing expression of WT1 was related to pathological type,clinical stage,histological differentiation,with ascites,and lymph node metastasis(P<0.05).Conclusion Low expression of RASSF1A and high expression of WT1 may be related to recurrent epithelial ovarian cancer.

Postrecurrence Clinical Outcome of Patients with Stage I Epithelial Ovarian Cancer Who Underwent Fertility-Sparing Surgery Compared to Those with Radical Surgery

Background: To examine the difference in the survival of patients with recurrent ovarian cancer who received fertility-sparing surgery (FSS) and those receiving radical surgery. Methods: Clinicopathologic data on a total of 90 patients with stage I recurrent ovarian cancer collected under the central pathological review system were subjected to survival analyses. Patients were divided into 2 groups: 1) FSS (N = 11), 2) Radical (N = 79). Results: Five-year overall survival rates of patients in the two groups were as follows: 40.8% (FSS)/44.2% (Radical), respectively. There was no significant difference in overall survival among the groups (P = 0.887). Additionally, three-year postrecurrence survival rates of patients in the two groups were 24.8% (FSS) and 25.3% (Radical) (P = 0.730). Furthermore, we accumulated 137 patients {FSS (N = 58), Radical group (N = 79)} with stage I recurrent ovarian cancer from the current study and six representative reports in the literature. Patients who experienced recurrence in the remaining ovary alone (FSS) showed a more favorable prognosis than those who had extra-ovarian site recurrence (overall survival: P = 0.021, postrecurrence survival: P = 0.069). Conclusions: Although our retrospective analysis was very preliminary, we could propose the hypothesis that patients with stage I recurrent ovarian cancer who undergo FSS may not show poorer survival rates than patients who receive radical surgery.

Overexpression and Immunosuppressive Functions of Transforming Growth Factor 1,Vascular Endothelial Growth Factor and Interleukin-10 in Epithelial Ovarian Cancer

Objective： Transforming growth factor-1 （TGF-βI）, vascular endothelial growth factor （VEGF）, and interleukin-lO （IL-10） may be critical cytokines in the microenvironment of a tumor, playing roles in immune suppression. This study was conducted to elucidate the roles and immunosuppressive functions of these cytokines in epithelial ovarian cancer （EOC）. Methods： The expression levels of TGF-β1, VEGF and IL-10 in malignant tissue were evaluated by immune- histochemistry and compared with corresponding borderline, benign, and tumor-free tissues. Moreover, relationships among the levels of these cytokines and correlations between expression and the prognosis of EOC were analyzed by Pearson rank correlations and multi-factor Logistic regression. The roles of TGF-βI, VEGF, and IL-lO in the immunosuppressive microenvironment of ovarian cancer were studied through dendritic cell （DC） maturation and CD4＋CD25＋FoxP3＋ Treg generation in vitro experiments. Results： TGF-β1, VEGF, and IL-IO were expressed TGF-β1 was an independent prognostic factor for EOC n 100%, 74.69%, and 54.96% of EOC patients, respectively. L-IO was significantly co-expressed with VEGF. In vitro, VEGF and TGF-β31 strongly interfered with DC maturation and consequently led to immature DCs, which secreted high levels of IL-IO that accumulated around the tumor site. TGF-β1 and IL-10 induced Treg generation without antigen presentation in DCs. Conclusions： TGF-βI, VEGF and IL-IO play important roles in EOC and can lead to frequent immune evasion events.

PGC-la induces apoptosis in human epithelial ovarian cancer cells through a PPARy-dependent pathway

Peroxisome proliferator-activated receptor gamma （PPAR）,） coactivator-1 alpha （PGC-1α） coactivates multiple transcription factors and regulates several metabolic processes. The current study investigated the role of PGC-1α in the induction of apoptosis in human epithelial ovarian cancer cells. The PGC-1α mRNA level between human ovaries and human ovarian epithelial tumors was examined by quantitative RT-PCR. Less PGC- 1α expression was found in the surface epithelium of malignant tumors compared with normal ovaries. Overexpression of PGC-1α in human epithelial ovarian cancer cell line Ho-8910 induced cell apoptosis through the coordinated regulation of Bcl-2 and Bax expression. Microarray analyses confirmed that PGC-1α dramatically affected the apoptosis-related genes in Ho-8910 cells. Mitochondrial functional assay showed that the induction of apoptosis was through the terminal stage by the release of cytochrome c. Furthermore, PG-C- 1 α-induced apoptosis was partially, but not completely, blocked by PPAR）, antagonist （GW9662）, and suppression of PPAR）, expression by siRNA also inhibited PGC-1α-induced apoptosis in Ho-8910 cells. These data suggested that PGC-1α exerted its effect through a PPARγ-dependent pathway. Our findings indicated that PGC-1α was involved in the apoptotic signal transduction pathways and downregulation of PGC-1α may be a key point in promoting epithelial ovarian cancer growth and progression.

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

IGHG1 promotes motility likely through epithelial-mesenchymal transition in ovarian cancer

Objective： Ovarian cancer（OC） is one of the leading causes of death for female cancer patients. COC166-9 is an OC-specific monoclonal antibody and we have identified immunoglobulin γ-1 heavy chain constant region（IGHG1） as its antigen. We explore the function of IGHG1 in proliferation, apoptosis and motility of OC cells further in this research.Methods： IGHG1 expression in OC specimens was detected through immunohistochemistry. Real-time quantitative polymerase chain reaction（RT-q PCR） or western blotting assay was used to test IGHG1 expression in OC cells. Viability of OC cells was tested by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT）assay. Flow cytometry or western blotting assay was used to detect cell cycle and apoptosis. Cellular motility was analyzed by using transwell assay and the markers of epithelial-mesenchymal transition（EMT） were tested through immunoblots.Results： Although it exerts negligible effect on the viability and apoptosis of OC cells, IGHG1 could promote migration and invasion of malignant cells in vitro. Mechanistically, IGHG1 increases the expression of N-cadherin and Vimentin while decreases E-cadherin expression. Additionally, IGHG1 expression in OC specimens is higher relative to the paired normal counterparts. Further analysis demonstrates that the increased IGHG1 expression correlates positively with the lymph node metastasis of OC.Conclusions： IGHG1 promotes the motility of OC cells likely through executing the EMT program. Increased IGHG1 expression in OC specimens is associated with the lymph node metastasis.

Epithelial ovarian cancer:An overview

Ovarian cancer is the second most common gyneco-logical cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.

Establishment of an optimized CTC detection model consisting of EpCAM,MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics

Objective:Emerging studies have demonstrated the promising clinical value of circulating tumor cells(CTCs)for diagnosis,disease assessment,treatment monitoring and prognosis in epithelial ovarian cancer.However,the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards.Methods:We enrolled 160 patients with epithelial ovarian cancer as the experimental group,and 90 patients including 50 patients with benign ovarian tumor and 40 healthy females as the control group.We enriched CTCs with immunomagnetic beads targeting two epithelial cell surface antigens(EpCAM and MUC1),and used multiple reverse transcription-polymerase chain reaction(RT-PCR)detecting three markers(EpCAM,MUC1 and WT1)for quantification.And then we used a binary logistic regression analysis and focused on EpCAM,MUC1 and WT1 to establish an optimized CTC detection model.Results:The sensitivity and specificity of the optimized model is 79.4%and 92.2%,respectively.The specificity of the CTC detection model is significantly higher than CA125(92.2%vs.82.2%,P=0.044),and the detection rate of CTCs was higher than the positive rate of CA125(74.5%vs.58.2%,P=0.069)in early-stage patients(stage I and II).The detection rate of CTCs was significantly higher in patients with ascitic volume≥500 mL,suboptimal cytoreductive surgery and elevated serum CA125 level after 2 courses of chemotherapy(P<0.05).The detection rate of CTC;and CTC;was significantly higher in chemo-resistant patients(26.3%vs.11.9%;26.4%vs.13.4%,P<0.05).The median progression-free survival time for CTC;patients trended to be longer than CTC;patients,and overall survival was shorter in CTC;patients(P=0.043).Conclusions:Our study presents an optimized detection model for CTCs,which consists of the expression levels of three markers(EpCAM,MUC1 and WT1).In comparison with CA125,our model has high specificity and demonstrates better diagnostic values,especially for early-stage ovarian cancer.Detection of CTC;and CTC;had predictive value for chemotherapy resistance,and the detection of CTC;suggested poor prognosis.

Association of serum lipids and severity of epithelial ovarian cancer：an observational cohort study of 349 Chinese patients

While obesity and fat intake have been associated with the risk and prognosis of epithelial ovarian cancer, the association between the lipid levels and epithelial ovarian cancer phenotype remains controversial. We conducted a retrospective study of 349 epithelial ovarian cancer patients who received treatment at Jiangsu Cancer Hospital, China between 2011 and 2017. We analyzed age at diagnosis, blood pressure, plasma glucose content, body mass index（BMI）, lipid levels and clinical parameters. Severity of epithelial ovarian cancer was classified according to the International Federation of Gynecology and Obstetrics（FIGO） grading system. Univariate analysis of the clinical factors according to the severity of epithelial ovarian cancer was followed by logistic regression analysis to identify clinical factors significantly associated with epithelial ovarian cancer severity. Univariate analysis indicated that age,BMI, triglyceride（TG）, and high density lipoproteins（HDL） differed significantly among different stages of epithelial ovarian cancer（P〈0.05）. In the logistic regression model, elevated TG（OR： 1.883; 95% CI= 1.207-2.937）, and low HDL（OR： 0.497; 95% CI = 0.298-0.829） levels were significantly associated with the high severity epithelial ovarian cancer. Our data indicate that high TG and low HDL levels correlate with a high severity of epithelial ovarian cancer. These data provide important insight into the potential relationship between the lipid pathway and epithelial ovarian cancer phenotype and development.

Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways

Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells.Among these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian cancer.Mechanistically,DSF treatment significantly reduced the expression of the anti-apoptosis marker Bcell lymphoma/leukemia-2(Bcl-2)and increase the expression of the apoptotic molecules Bcl2 associated X(Bax)and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis.Furthermore,DSF is a newly identified effective copper ionophore,thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment.Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins(biomarkers of cuproptosis).In vivo,DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model.Thus,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.

Expression and mechanism of action of miR-196a in epithelial ovarian cancer

Objective:To explore the expression,biological function and possible mechanism of action of microRNA molecular-196a(miR-196a) in epithelial ovarian cancer.Methods:RT-PCR was used to detect the expression quantities of epithelial ovarian tissue,benign ovarian tissue,normal ovary epithelial tissue,ovarian cancer cell lines and miR-196 a in normal ovarian epithelial cells to analyze the relationship between the expression of miR-196 a and the clinical pathologic parameters of ovarian cancer.Among those cell lines,the cell line of which miR-196 a expressed the most or least was selected and transfected the ovarian cancer cell line by using negative control plasma and miR-196 a inhibitor.After transfection,RT-PCR was used to test the expression quantity of miR-196 a,Transwell chamber method was applied to determine the migration and invasion abilities of ovarian carcinoma cells and Western blot was employed to detect the expression of HOXA10 protein.Results:The relative expression quantities of miR-196 a in ovarian cancer tissue and benign ovarian tissue were significantly higher than that in normal ovarian epithelial tissue,and the expression quantity of miR-196 a in ovarian cancer tissue was distinctively higher than that in benign ovarian tissue(P < 0.05).Among 78 cases of epithelial ovarian cancer,the expression quantities of miR-196 a in patients with low differentiation were all significantly higher than those in patients with high differentiation(P< 0.05).The expression of miR-196 a showed no significant relation with age,clinical stage and whether CA125 was positive or not in patients(P > 0.05).Compared with normal ovarian epithelial cell line IOSE80,the expression quantities of miR-196 a of all ovarian cancer cell lines increased obviously and differences were statistically significant(P < 0.05).Among them,the expression of miR-196 a of ovarian cancer cell line SKOV3 was the highest,while it decreased significantly(4.678 ± 0.785 vs.2.131 ± 0.345,t = 2.938,P < 0.05) after the ovarian cancer cell line SKOV3 was transfected by miR-196 a inhibitor.The results of Transwell chamber method showed that the migration and invasion abilities of ovarian cancer cells SKOV3 were declined significantly after the expression of miR-196 a was down-regulated and the difference showed statistical significance(P < 0.05).The results of Western blot revealed that the relative expression of HOXA10 decreased distinctly after the expression of miR-196 a was down-regulated and also the difference showed statistical significance(P < 0.05).Conclusions:The miR-196 a might serve as a cancer-promoting gene to promote the migration and invasion of epithelial ovarian cancer by downstream target gene HOXA10.

Relationship between the Expression of Thymidylate Synthase,Thymidine Phosphorylase and Dihydropyrimidine Dehydrogenase and Survival in Epithelial Ovarian Cancer

The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-PCR (Taqman) was used to detect the mRNA expression of TS, TP and DPD in formalin-fixed and paraffin-embedded 106 samples of epithelial ovarian cancer and 29 normal ovaries. A TATA box-binding protein (TBP) was used as an endogenous reference gene. A relationship between TS, TP, DPD expression and clinicopathologic features was investigated. The protein location and expression of TS, TP and DPD was examined in the same patients by an avidin-biotin-peroxidase immunohistochemistry. TS and TP mRNA expression levels were significantly higher in tumor group than in normal controls, with the average value of TS and TP mRNA being 6.14±0.62 and 0.59±0.06 in tumor tissue, and 0.71±0.14 and 0.16±0.04 in normal tissue, respectively. DPD mRNA expression levels were significantly lower in tumor group (0.11±0.02) than in normal controls (0.38±0.05). There was statistically significant difference in TS and TP mRNA expression levels among different pathological grades and clinical stages (P<0.05), but histological subtype was not significantly associated with TS and TP mRNA expression. DPD gene expression was not significantly associated with any clinicopathological parameters. Immunohistochemistry revealed that TP protein was mainly distributed in nucleus, and TS and DPD mainly in cytoplasm. The protein expression intensity of TS, TP and DPD was coincided with the mRNA expression levels. It was concluded that TS, TP mRNA and protein expression levels were significantly higher in epithelial ovarian cancer, and DPD mRNA and protein expression levels were significantly lower. The expression levels of TS and DPD were related to the patients’ prognosis and survival. Combined gene expression levels of TS, TP and DPD represent a new variable to predict the clinical outcome in ovarian cancer. The association of TS, TP and DPD expression levels with survival suggests an importance of these genes for tumor occurrence and progression.

Trabectedin therapy as an emerging treatment strategy for recurrent platinum-sensitive ovarian cancer

Epithelial ovarian cancer(OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer(ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies.