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BackgroundClinically, few patients with locally advanced cervical cancer (LACC) are insensitive to neoadjuvant chemotherapy (NACT). Recent studies have reported that circulating microRNAs (miRNAs) may be involved in the response to NACT. The aim of this study was to discover the potential miRNAs that can predict the response to NACT in LACC.MethodsPair-matched blood samples of 39 LACC patients before and after receiving NACT were collected. Seven paired samples were used for microRNA microarray analysis. Targeted miRNAs were selected by bioinformatics analysis and were validated by quantitative reverse transcription–polymerase chain reaction (qRT-PCR). All 39 patients were assigned into either the responders group or the non-responders group after NACT. The predictive performance of selected microRNA was evaluated by sensitivity, specificity, accuracy, and the area under the receiver operating characteristic (ROC) curve.ResultsA total of 17 miRNAs downregulated before NACT and upregulated after NACT were selected according to microarray analysis in our previous study, and miR-326 and miR-376a-3p were selected for further exploration. According to the responses and the evaluation criteria, 25 patients reached partial response (PR) and 14 patients remained stable. Further qRT-PCR analysis showed that miR-326 significantly downregulated before NACT and upregulated after NACT in 12 responders (p = 0.02). The expression of miR-376a-3p showed no statistical difference before and after NACT in these 12 responders. Then, miR-326 provided an AUC-ROC of 0.75 (p = 0.04) in the discrimination between the responders and non-responders groups. The cutoff value of ROC for miR-326 to predict the response of NACT was ConclusionsThe expression of miR-326 significantly upregulated after NACT in responders. miR-326 may be a biomarker for predicting the response to NACT in LACC patients. The results may optimize individualized treatments for LACC patients.

OBJECTIVE To externally validate the performance of the Mayo triage algorithm applied to treatment strategy management in advanced epithelial ovarian cancer (AEOC) patients. METHODS AEOC patients who underwent primary debulking surgery (PDS) were included and were divided into two groups based on the Mayo triage algorithm: "high risk" and "triage appropriate". The surgery outcomes and complications of the patients were compared between the two groups. RESULTS 179 consecutive AEOC patients were enrolled for analysis, including 32 patients in the high-risk group and 147 patients in the triage-appropriate group. The results showed that patients in the high-risk group were older, had worse physical status and had lower preoperative serum albumin than those in the triage-appropriate group (P

BackgroundFrailty has been related with poor prognosis of various diseases, including ovarian cancer. We performed a systematic review and meta-analysis to evaluate the association between frailty and long-term survival of patients with ovarian cancer.MethodsRelevant cohort studies were retrieved by search of PubMed, Embase, Cochrane’s Library, and Web of Science electronic databases. Two authors independently performed literature search, data collection, and statistical analyses. A random-effect model incorporating the possible influence of heterogeneity was used to pool the results.ResultsNine cohort studies including 2497 women with confirmed diagnosis of ovarian cancer contributed to the meta-analysis, and 536 (21.5%) of them were with high frailty. The median follow-up durations varied between 24 and 69 months. Compared to patients with low or non-frailty, OC patients with high frailty were associated with poor overall survival (risk ratio [RR]: 1.61, 95% confidence interval [CI]: 1.41 to 1.85, p < 0.001; I2 = 0%) and progression-free survival (RR: 1.51, 95% CI: 1.20 to 1.89, p < 0.001; I2 = 0%). Subgroup analyses according to study design, cancer stage, age of patients, scales for frailty evaluation, follow-up duration, and quality score of the included study showed consistent association between high frailty and poor overall survival in women with ovarian cancer (p for subgroup effects all < 0.05). After considering GRADE criteria for strength of the evidence, it was rated low for both the two outcomes.ConclusionHigh frailty may be an independent risk factor of poor survival in women with ovarian cancer. Evaluating frailty may be important for predicting the prognosis and determining the optimal anticancer treatments in women with ovarian cancer.Systematic Review Registrationhttps://inplasy.com/, identifier INPLASY202290028.

ObjectiveTo establish nomograms to predict the risk of postoperative complications following cytoreductive surgery in patients with advanced epithelial ovarian cancer (AEOC).MethodsA multicenter retrospective cohort study that included patients with FIGO stage IIIC-IV epithelial ovarian cancer who underwent cytoreductive surgery was designed. By using univariate and multivariate analyses, patient preoperative characteristics were used to predict the risk of postoperative complications. Multivariate modeling was used to develop Nomograms.ResultsOverall, 585 AEOC patients were included for analysis (training cohort = 426, extrapolation cohort = 159). According to the findings, the training cohort observed an incidence of postoperative overall and severe complications of 28.87% and 6.10%, respectively. Modified frailty index (mFI) (OR 1.96 and 2.18), FIGO stage (OR 2.31 and 3.22), and Surgical Complexity Score (SCS) (OR 1.16 and 1.23) were the clinical factors that were most substantially associated to the incidence of overall and severe complications, respectively. The resulting nomograms demonstrated great internal discrimination, good consistency, and stable calibration, with C-index of 0.74 and 0.78 for overall and severe complications prediction, respectively. A satisfactory external discrimination was also indicated by the extrapolation cohort, with the C-index for predicting overall and severe complications being 0.92 and 0.91, respectively.ConclusionsThe risk of considerable postoperative morbidity exists after cytoreductive surgery for AEOC. These two nomograms with good discrimination and calibration might be useful to guide clinical decision-making and help doctors assess the probability of postoperative complications for AEOC patients.

ObjectiveTo study the correlation between BRCA mutation status and the risk of adverse reactions in patients with ovarian cancer.MethodA real-world study was conducted at the largest gynecological oncology center in western China, the West China Second University Hospital of Sichuan University. The research subjects were patients diagnosed with ovarian cancer who were initially treated in our hospital from January 2016 to January 2020 and had their BRCA gene status evaluated. Multivariate Cox analysis was conducted to investigate the correlation between the BRCA mutation status and adverse reactions in ovarian cancer patients during initial treatment.ResultsA total of 349 ovarian cancer patients were enrolled, including 79 patients with pathogenic BRCA variants, resulting in a pathogenic mutation rate of 22.6%. Among these 79 patients, 57 had BRCA1 variants and 22 had BRCA2 variants, yielding a pathogenic mutation rate of 16.3% and 6.3%, respectively. Multivariate COX analysis revealed that pathogenic BRCA variants were not related to the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs (P>0.05), during the initial treatment of ovarian cancer.ConclusionBRCA variants did not increase the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, in ovarian cancer patients during initial treatment.

Background The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging guideline for cervical cancer includes stage IIIC recognized by preoperative radiology (IIIC-r) to state there are lymph nodes metastases (LNM) identified by imaging tools. We aim to explore the reasonability and limitations of stage IIIC-r and try to explore the potential reasons. Methods Electronic medical records were used to identify patients with cervical cancer. According to the new staging guidelines, patients were reclassified and assigned into five cohorts: stage I, stage II, stage IIIC-r, LNM confirmed by pathology (IIIC-p) and LNM detected by radiology and confirmed by pathology (IIIC r + p). Five-year overall survivals were estimated for each cohort. The diagnosis accuracy of computed tomography (CT), magnetic resonance imaging (MRI) and diameter of detected lymph nodes were also evaluated. Results A total of 619 patients were identified. The mean follow-up months were 65 months (95% CI 64.43–65.77) for all patients. By comparison, the 5-year overall survival rates were not statistically different (p = 0.21) among stage IIIC-r, stage I and stage II. While, the rates were both statistical different (pp = 0.05). Conclusions It seems that the FIGO 2018 staging guideline for cervical cancer is likely to has certain limitations for the classification of those with LNM. CT or MRI, however, has limitations on detecting LNM. It would be better to use more accurate imaging tools to identify LNM in the clinical practices.

This updated meta-analysis sought to explore whether pretreatment neutrophil-to-lymphocyte ratio (NLR) could serve as an independent predictor for survival outcomes in patients with cervical cancer. We searched PubMed, Embase, Web of science and Scopus for studies on the association of pretreatment serum NLR with overall survival (OS) and progression-free survival (PFS) among patients with cervical cancer. Included studies with a hazard ratio (HR) and 95% confidence interval (CI) or a p-value were weighted by generic inverse-variance and pooled in a random effects meta-analysis. Subgroup analyses were conducted according to regions, NLR cut-off values and treatments. Publication bias was analyzed by Egger’s and Begg’s tests. A total of 14 studies comprising 6041 patients were included. The median cut-off value for NLR was 2.46 (range from 1.60 to 3.80). The higher NLR was associated to worse OS (HR 1.86, 95% CI 1.44–2.40) and PFS (HR 1.67, 95% CI 1.25–2.23), compared with lower NLR. This association still exited when analyzed according to regions, NLR cut-off values. Moreover, Significant association between NLR and OS was observed in studies which included patients with early stage disease and receiving radical surgeries. High NLR is independently associated with decreased OS and PFS in patients with cervical cancer. Pretreatment NLR is of independent value to predict the survival outcomes in patients with cervical cancer, regardless of regions and primary treatments.

ObjectiveThis study evaluated the oncologic outcomes of laparoscopy and laparotomy in the management of early-stage ovarian cancer patients.MethodsWe conducted an observational study of women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage I ovarian cancer who underwent surgery at the West China Second University Hospital from 2012 to 2020. Patients who received adjuvant chemotherapy before surgery, those with non-epithelial histopathological types, or those with insufficient data were excluded. Using propensity score matching, data from consecutive laparoscopic patients treated by laparoscopy were matched 1:2 with a cohort of patients undergoing open surgery. The operative and survival outcomes among the matched cohorts were examined using the Kaplan–Meier method.ResultsAmong 200 eligible patients, 74 patients undergoing laparoscopy were compared with a cohort of 126 patients undergoing open surgery. Baseline characteristics were similar between groups after matching. Patients who had laparoscopy had a shorter operative time (P = 0.001), a shorter hospital stay (P ConclusionsThere is no difference in prognosis between laparoscopic and open surgery in women with stage I epithelial ovarian cancer. Laparoscopic treatment of early-stage ovarian cancer is safe and feasible for stage I epithelial ovarian cancer patients.

IntroductionWe aimed to evaluate poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) regimens in BRCA-mutated ovarian cancer for patients responsive to front-line platinum (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) or platinum-sensitive relapsed (olaparib, rucaprib, niraparib) patients in phase III randomized controlled trials.MethodsA network meta-analysis was utilized to generate the direct and indirect comparisons. The primary outcomes for network meta-analysis were efficacy (hazard ratios for progression-free survival in BRCA mutation cohort) and toxicity (odds ratios for all grade 3–4 adverse events). The American Society of Clinical Oncology (ASCO) value framework was used to assess the cost-effectiveness of the PARPi regimens.ResultsNetwork meta-analysis indicated no statistically significant differences in efficacy and toxicity among the assessed upfront or relapsed PARPi regimens (95% CI included 1). The ASCO value framework indicated that current PARPi regimens were similar in clinical benefits, toxicity, and net health benefit in the upfront (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) and relapsed setting (olaparib, rucaprib, niraparib). The addition of bevacizumab to olaparib ($353.72) increased the cost per unit net health benefit for patients compared with olaparib monotherapy ($260.57). The upfront PARPi regimens had lower toxic scores than the regimens used at relapse.ConclusionsThe choice of PARPi regimens both in the upfront and relapsed setting should consider not only efficacy and toxicity but also costs in BRCA mutation patients. Current combining PARPi regimens are not recommended for such patients in the upfront setting from the cost-effective perspective. Upfront PARPi regimens are less toxic than those used at relapse.

Background This study aimed to evaluate the effect of clinicopathologic and surgical factors on the prognosis and fertility outcomes of patients with borderline ovarian tumour (BOT). Methods We performed a retrospective analysis of BOT patients who underwent surgical procedures in West China Second University Hospital from January 2008 to January 2015. The disease-free survival (DFS) outcomes and potential prognostic factors were evaluated using the Kaplan-Meier method and Cox regression analysis, respectively. Furthermore, fertility outcomes were analysed using Pearson Χ 2 and Fisher’s correlation tests. Results A total of 448 patients were included, with a median age of 37.1 years and a median follow-up time of 113 months; 52 (11.6%) recurrences were observed, with a mean recurrence interval of 80.2 months and four (0.9%) deaths; 118 (26.3%) patients underwent staging surgery and the remaining 330 (73.7%) underwent unstaged surgery. In total, 233 patients undergoing fertility-sparing surgery (FSS) attempted to conceive, and 92 (39.48%) of them achieved pregnancy. No significant differences in fertility outcomes were found between the staging and unstaged surgery groups ( P = 0.691). In univariate analysis, staging surgery was associated with DFS (hazard ratio [HR] = 2.191; P = 0.005), but it was not an independent prognostic factor ( P = 0.600) for DFS on multivariate analysis. Multivariate Cox analysis revealed that advanced FIGO stage (≥stage II), positive ascites\pelvic washings, and laparotomy approach were independent prognostic factors for DFS in patients with BOT, whereas advanced stage (≥stage II), laparotomy approach, cystectomy-related procedures, invasive implants, and bilateral tumours were independent prognostic factors for DFS in patients undergoing FSS. In addition, laparoscopy resulted in better prognosis than laparotomy in patients with early-stage (stage I) tumours and a desire for fertility preservation. Conclusion Patients with BOT fail to benefit from surgical staging in terms of prognosis and fertility outcomes. Laparoscopy is recommended for patients with stage I disease who desire to preserve their fertility. Physicians should pay more attention to the risk of recurrence in patients who want to preserve fertility with advanced stage (≥stage II) disease, invasive implants, and bilateral tumours, and choose FSS carefully.

IntroductionRecently, the safety of minimally invasive surgery in the treatment of cervical cancer has been questioned. This study was designed to compare the disease-free survival and overall survival of abdominal radical hysterectomy and laparoscopic radical hysterectomy in patients with early-stage cervical cancer.MethodsA total of 1065 patients with early-stage cervical cancer who had undergone abdominal/laparoscopic radical hysterectomy between January 2013 and December 2016 in seven hospitals were retrospectively analyzed. The 1:1 propensity score matching was performed in all patients. Patients with tumor size ≥2 cm and 2 test were used for the comparison of continuous and categorical variables, respectively. The survival curves were generated by the Kaplan-Meier method and compared by log-rank test.ResultsAfter matching, a total of 812 patients were included in the disease-free survival and overall survival analyses. In the entire cohort, the laparoscopic radical hysterectomy group had a significantly shorter disease-free survival (HR 1.65, 95% CI 1.00 to 2.73; p=0.048) but not overall survival (HR 1.60, 95% CI 0.89 to 2.88; p=0.12) when compared with the abdominal radical hysterectomy group. In patients with tumor size ≥2 cm, the laparoscopic radical hysterectomy group had a significantly shorter disease-free survival (HR 1.93, 95% CI 1.05 to 3.55; p=0.032) than the abdominal radical hysterectomy group, whereas no significant difference in overall survival (HR 1.90, 95% CI 0.95 to 3.83; p=0.10) was found. Additionally, in patients with tumor size ConclusionLaparoscopic radical hysterectomy was associated with inferior disease-free survival compared with abdominal radical hysterectomy in the entire cohort, as well as in patients with tumor size ≥2 cm. For the surgical treatment of patients with early-stage cervical cancer, priority should be given to open abdominal radical hysterectomy.

Background Homeobox B4 (HOXB4) is correlated with poor prognosis of various cancer types. However, how HOXB4 promotes ovarian cancer (OV) progression remains unclear. Methods The Cancer Genome Atlas (TCGA) database indicated that a high level of HOXB4 in OV was correlated with poor prognosis. The biological functions of HOXB4 were confirmed by colony formation, migration, and invasion assays. The effect of HOXB4 on the expression of EMT cell markers was determined. The transcriptional target of HOXB4 was DHDDS, which was detected by a ChIP assay. A xenograft tumor model was generated in nude mice to detect the role of HOXB4 in tumor proliferation and metastasis. Results The results showed that HOXB4 protein levels were higher in OV tissues than in normal tissues and correlated with poor prognosis of OV. HOXB4 reduction inhibited the proliferation and invasion ability of OV cells in vitro. Conversely, these effects were enhanced by the upregulation of HOXB4 in OV cells. The binding of HOXB4 to two DNA motifs regulated DHDDS expression and contributed to the malignant progression of OV. The role of HOXB4 in contributing to tumor development in vivo was verified in mice. Further results indicated that HOXB4 induced Snail and Zeb1 expression. Conclusion Overall, HOXB4 overexpression was remarkably correlated with poor prognosis of OV. Mechanistically, HOXB4 enhances the proliferation and invasion of tumor cells by activating DHDDS, thereby promoting the malignant progression of OV.

Poly ADP-ribose polymerase inhibitor (PARPi) has become an important maintenance therapy for ovarian cancer after surgery and cytotoxic chemotherapy, which has changed the disease management model of ovarian cancer, greatly decreased the risk of recurrence, and made the prognosis of ovarian cancer better to certain extent. The three PARPis currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ovarian cancer are Olaparib, Niraparib and Rucaparib. With the incremental results from new clinical trials, the applicable population of PARPi for ovarian cancer have expanded to population with non-BRCA mutations. Although BRCA mutated population are still the main beneficiaries of PARPi, recent clinical trials indicated PARPis’ therapeutic potential in non-BRCA mutated population, especially in homologous recombination repair deficiency (HRD) positive population. However, lack of unified HRD status detection method poses a challenge for the accurate selection of PARPi beneficiaries. The reversal of homologous recombination (HR) function during the treatment will not only cause resistance to PARPis, but also reduce the accuracy of the current method to determine HRD status. Therefore, the development of reliable HRD status detection methods to determine the beneficiary population, as well as rational combination treatment are warranted. This review mainly summarizes the latest clinical trial results and combination treatment of PARPis in ovarian cancer with non-BRCA mutations, and discusses the application prospects, including optimizing combination therapy against drug resistance, developing unified and accurate HRD status detection methods for patient selection and stratification. This review further poses an interesting topic: the efficacy and safety in patients retreated with PARPis after previous PARPi treatment---“PARPi after PARPi”.

PurposeTo compare the clinical outcomes of patients with early-stage cervical cancer who underwent minimally invasive surgery (MIS) by surgeons in different phases and evaluate whether the proficiency of surgeons affects the survival outcomes.Materials and MethodsA total of 851 patients with early-stage cervical cancer who underwent radical hysterectomy between January 2008 and June 2018 (every year from January to June) at a tertiary hospital were retrospectively analyzed. We categorized patients into four phases according to their sequence (phase one, 1-10 cases; phase two: 11-20 cases; phase three: 21-30 cases; phase four: > 30 cases). Demographics and clinical and pathological data were collected and analyzed.ResultsThere were no statistical differences between the open surgery and MIS groups regarding three- and five-year overall survival (OS) and disease-free survival (DFS). The OS and DFS of patients in the MIS group in phase one were significantly lower than those in later phases and those in the open surgery group after adjustment (OS, P = 0.009; HR, 2.896; 95%CI, 1.303-6.435; DFS, P = 0.009; HR, 2.712; 95%CI, 1.289-5.706). Survival outcomes were not statistically significant when comparing different surgeons.ConclusionThe phase one cases of MIS had lower OS and DFS than those in later phases and those in the open surgery group. Thus, we suggest that the proficiency of surgeons is associated with survival outcomes of MIS. Favorable outcomes can be obtained after a certain number of MIS cases.

The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) is a molecular classification system that identifies endometrial cancer (EC) into four prognostically distinct subtypes: POLE-mutated, mismatch repair deficiency (MMR-D), p53 wild-type (p53wt), and p53 abnormal (p53abn). However, few reports have applied the ProMisE classifier to EC patients who underwent fertility-preserving treatment (FPT) so far. This study evaluated whether the ProMisE classifier predicted in early-stage EC patients after FPT. We first summarized the three reported outcomes of ProMisE applied to EC patients who received FPT. The hormone-treated patients with EC from 2010 to 2020 in our facility were then analyzed. By sequential immunohistochemistry and Sanger sequencing of POLE according to the ProMisE system, formalin-fixed paraffin-embedded blocks of patients before treatment were collected and classified into POLE-mutated, MMR-D, p53wt, and p53abn subtypes. The primary outcome was a complete response rate after FPT. Thirteen patients were enrolled from our facility, with 3 (3/13) MMR-D, 0 (0/13) POLE, 8 (8/13) p53wt, 1 (1/13) p53abn, and 1 (1/13) failed with DNA amplification. Six (6/8) patients with p53wt, 2 (2/3) patients with MMR-D, and 1 (1/1) patient with p53abn achieved a complete response in 6 months after treatment. The results of our study and the reported outcomes were finally combined. A total of 106 patients who underwent FPT were included. Of these, 23 (21.7%) were classified as MMR-D, 3 (2.8%) as POLE-mutated, 3 (2.8%) as p53abn, and 77 (72.6%) as p53wt. There was no significant difference in the complete response rate (P = 0.152) and recurrence rate (P = 0.174) between MMR-D and p53wt subtypes after FPT. Based on current data, we observed no prognostic significance of the ProMisE classifier in EC patients who underwent FPT. Larger prospective studies are needed to elucidate the precise prognostic meaning of this molecular classifier in these cases.

The most advanced epithelial ovarian cancer develops recurrent disease despite maximal surgical cytoreduction and adjuvant platinum-based chemotherapy. Treatment with secondary cytoreductive surgery (SCS) combined with chemotherapy or with chemotherapy alone for patients with platinum-sensitive recurrent ovarian cancer (ROC) is currently under heated discussion. Encouragingly, the results of the AGO DESKTOP III Study and the SOC1/SGOG-OV2 trial, which have been published recently, showed a striking advantage in terms of overall survival (OS) and progression-free survival (PFS) of ROC patients undergoing SCS compared to chemotherapy alone; moreover, a benefit of SCS exclusively for patients with complete gross resection (CGR) was particularly highlighted. CGR is considered the ultimate goal of SCS, on condition that the balance between maximal survival gain and minimal operative morbidity is maintained. Several models have been proposed to predict the rate of CGR, such as the MSK criteria, the AGO score, and the Tian model, over the last 15 years. This summary is mainly about the several previously published prediction models for CGR in SCS of ROC patients and discusses the effectiveness and limitations of these prediction models.

MicroRNAs (miRNAs) have emerged as important regulators of bone development and regeneration. The aim of the present study was to determine whether miR-203a-3p.1 is involved in osteogenic differentiation of multiple myeloma (MM)-mesenchymal stem cells (MSCs) and the potential underlying mechanism. MSCs were isolated from patients with MM and normal subjects and confirmed by flow cytometry using specific surface markers. The osteogenic differentiation capacity of MM-MSCs was identified by Alizarin Red S calcium deposition staining and reverse transcription-quantitative PCR (RT-qPCR) of typical osteoblast differentiation markers. The role of miR-203a-3p.1 in the osteoblast differentiation of MM-MSCs was determined by gain or loss of function experiments. The target of miR-203a-3p.1 was identified using bioinformatics (including the miRNA target prediction database TargetScan, miRDB, DIANA TOOLS and venny 2.1.0), luciferase reporter assay, RT-qPCR and western blotting. The expression levels of proteins involved in the Wnt3a/β-catenin signaling pathway were detected by western blot analysis. The results revealed that the osteogenic differentiation capacity of MM-MSCs was reduced when compared with normal (N)-MSCs, as demonstrated by a decrease in calcium deposition and mRNA expression of typical osteoblast differentiation markers, including ALP, OPN and OC. In addition, miR-203a-3p.1 was downregulated in N-MSCs following osteoblast induction, whereas no changes were observed in MM-MSCs. The downregulation of miR-203a-3p.1 resulted in increased osteogenic potential, as indicated by the increase in the mRNA expression levels of the typical osteoblast differentiation markers, including alkaline phosphatase (ALP), osteopontin (OPN) and osteocalcin (OC). Bioinformatics and luciferase reporter assay analysis indicated that mothers against decapentaplegic homolog 9 (Smad9) may be a direct target of miR-203a-3p.1 in N-MSCs. The RT-qPCR and western blot assays revealed that overexpression of smad9 significantly enhanced the effect of miR-203a-3p.1 inhibitors on osteoblast markers, which indicated that miR-203a-3p.1 inhibitors may regulate the osteogenic differentiation of MM-MSCs by upregulating Smad9. In addition, the Wnt3a/β-catenin signaling pathway was activated following miR-203a-3p.1 inhibition. These results suggest that miR-203a-3p.1 may serve an important role in the osteogenic differentiation of MM-MSCs by regulating Smad9 expression.

Background MiRNAs are considered to be significant contributors to the pathogenesis of psychiatric diseases, but little is known about the potential roles of miRNAs in the treatment effect of panic disorder (PD). Therefore, we aimed to identify the miRNAs association with PD over the course of sertraline treatment. Methods Sixty-seven patients were collected for a 6-week period of sertraline treatment, and evaluated using HAMD-17, HAMA-14 and PDSS both at the baseline and 6 weeks later. Blood samples were collected before and after treatment, respectively. Ten pairs of samples were analyzed using miRNA array, and the differentially expressed miRNAs were further validated using RT-PCR in the whole sample. Results miR-451a, miR-144-5p, miR-25-3p and miR-660-5p were found to be significantly up-regulated, while miR-1 and miR-148-5p significantly down-regulated after sertraline treatment. The change of miR-25-3p before and after treatment (△miR-25-3p) was positively related to both the changes of PDSS3 scores (△PDSS3) (p = 0.017, 31.5% contribution) and △ PDSS7 (p = 0.016, 32.3% contribution). The △miR-660-5p was positively related to both the △HAMA5 (p = 0.03, 26% contribution) and △PDSS7 (p = 0.032). The △miR-148-5p was positively related to the △PDSS4 (p = 0.046, 21.5% contribution), but negatively related to the △HAMA13 (p = 0.005, 41.9% contribution). The △miR-144-5p was negatively related to the △HAMA9 (p = 0.032, 25.3% contribution). Conclusions These findings might provide some evidences to the involvement of miRNA in the effect of anti-anxiety agents, which contributed to the better understanding the disease and developing new therapeutic genetic targets.

Background: Ovarian clear cell carcinoma (OCCC) has a worse prognosis compared to other histological subtypes. Although the survival effect of lymph nodes ratio (LNR) on ovarian carcinoma have been elucidated in several studies, the prognostic effect of LNR in OCCC has not been separately studied. This study aimed to investigate the prognostic significance of LNR in FIGO stage III OCCC. Methods: Patients with FIGO stage III OCCC who underwent primary cytoreductive surgery and systematic lymphadenectomy from January 2008 to June 2014 in two independent hospitals were retrospectively reviewed. Two independent patients cohorts were used to investigate the survival impact of LNR by using Kaplan-Meier and Cox regression proportional hazard method. Results: In training cohort, the 5-year progression-free survival (PFS) rates was 32.4% for patients with LNR ≤ 25%, and 19.8% for patients with LNR > 25%, respectively (p = 0.017). The 5-year overall survival (OS) rates was 41.3% for patients with LNR ≤ 25%, and 25.8% for patients with LNR > 25%, respectively (p = 0.003). In multivariate analysis, increased LNR was correlated with a poorer DFS (HR = 2.12 ,95% CI 1.32-3.41, p = 0.002) and OS (HR = 2.29, 95% CI 1.37-5.12, p = 0.001). These results were verified in a validation cohort. Conclusions: LNR is an independent survival predictor in patients with FIGO stage III OCCC.

Background: Angiopoietin-like protein 4 (ANGPTL4) has been demonstrated highly expressed in some cancers, but it also was downregulated in others through DNA methylation. However, the expression status of ANGPTL4 in cancer of cervix remains unclear. Thus, our present study attempts to investigate the role of ANGPTL4 in the prognosis of patients with cervical cancer. Methods: Immunohistochemistry, western blotting and qRT-PCR were performed to investigate the expressive level of ANPGTL4 in cervical cancer tissues and paired noncancer tissues. The relationship of ANGPTL4 expression and clinicopathological factors was measured by Chi-square test. Overall and disease-free survival (OS and DFS) rates were estimated and compared by using Kaplan-Meier method and log-rank test, respectively. To assess the prognostic significance of ANGPTL4 in cervical cancer patients, the Cox regression model was utilized to process univariate and multivariate analyses. Results: ANGPTL4 was upregulated in cervical cancer samples and advanced tumor stage, deep stromal invasion, lymph node metastasis, lymphovascular space invasion, as well as poor OS and DFS were shown to be tightly correlated with it. Results of Cox multivariate analysis demonstrated that ANGPTL4 expression was an independent prognostic factor for OS and DFS in cervical cancer. Conclusion: Upregulated ANGPTL4 seems to be a useful marker for poor prognosis in cervical cancer.

PurposeTo analyze the potential prognostic factors of epithelial ovarian cancer (EOC) in women aged under 35 compared to those aged 60–79.MethodsCases were retrospectively obtained from SEER database. Clinical characteristics, such as race, histological type, AJCC stage, laterality of tumors, CA125 results, and surgical strategies, were analyzed in < 35 years group and 60–79 years group. Kaplan-Meier survival curves were used to evaluate overall survival (OS) and cause-specific survival (CSS). Cox proportional hazard model was used to identify the predictors for CSS.ResultsSixteen thousand eight hundred forty-seven EOC patients diagnosed in 2004–2015 were identified from SEER database, with 1,015 aged under 35 and 15,833 aged 60–79. In < 35 years group, mucinous (32.2%) was the most common histological type, followed by high-grade serous (26.6%) and endometrioid (18.3%), while in 60–79 years group, high-grade serous (68.3%) represented the leading histological type. Most young women were diagnosed at stage I (57.7%), while most old women were diagnosed at stage (48.1%). Both 5-year OS and 5-year CSS were higher in < 35 years group (5-year OS: 76.00% vs 40.18%, p < 0.001; 5-year CSS: 83.56% vs 55.18%, p < 0.001). The multivariate analysis identified histological type and stage as prognostic factors for CSS in both groups. Endometrioid represented a positive predictor for CSS, while carcinosarcoma and malignant Brenner were related to a worse CSS. (< 35 years group: carcinosarcoma vs endometrioid: HR 5.630, p=0.024; malignant Brenner vs endometrioid: HR 4.005, p < 0.001; 60–79 years group: carcinosarcoma vs endometrioid: HR 3.606, p < 0.001; malignant Brenner vs endometrioid: HR 2.291, p < 0.001). Tumors laterality, CA125 levels, surgery and lymphadenectomy failed to be associated with the CSS in < 35 years group, while found to be independent risk factors in 60–79 years group.ConclusionEOC women aged under 35 had a better survival outcome over EOC women aged 60–79, owing to high proportion of endometrioid and mucinous types in histology, as well as early-stage diagnosis. Identification of histological types and gene profiles should be underscored in young EOC patients.

Normal cells must overcome multiple protective mechanisms to develop into cancer cells. Their new capabilities include self-sufficiency in growth signals and insensitivity to antigrowth signals, evasion of apoptosis, a limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis; these are also termed the six hallmarks of cancer. A deep understanding of the genetic and protein alterations involved in these processes has enabled the development of targeted therapeutic strategies and clinical trial design in the search for ovarian cancer treatments. Clinically, significantly longer progression-free survival has been observed in the single use of PARP, MEK, VEGF and Chk1/Chk2 inhibitors. However, the clinical efficacy of the targeted agents is still restricted to specific molecular subtypes and no trials illustrate a benefit in overall survival. Exploring novel drug targets or combining current feasible biological agents hold great promise to further improve outcomes in ovarian cancer. In this review, we intend to provide a comprehensive description of the molecular alterations involved in ovarian cancer carcinogenesis and of emerging biological agents and combined strategies that target aberrant pathways, which might shed light on future ovarian cancer treatment.

Background: The pathogenesis and clinical behaviors between solitary leiomyoma (SL) and multiple leiomyomas (ML) vary, which lead to the difference in management for childbearing-aged patients. Herein, we aim to find the potential miRNA biomarkers for optimizing the individualized management between SL and ML.Methods: A microarray analysis was conducted to screen out the potentially dysregulated miRNAs. Target genes and signaling pathway potentially involved in UL pathogenesis were predicted by bioinformatics. The effect of miRNA was examined by Cell Counting Kit-8 proliferation assay and qRT-PCR after transfection of miRNA mimicsResults: The top 5 differentially expressed miRNAs, Wnt signalling pathway and its two central molecules APC and CTNNB1 were screened out according to microarray analysis and bioinformatics. MiR-142-3p was selected for further exploration. In validation of qRT-PCR, MiR-142-3p was significantly upregulated in SL, while downregulated in ML, CTNNB1 and sequencing target AXIN-2 were expressed at higher level in ML than SL. Overexpression of MiR-142-3p resulted in lower transcription level of CTNNB1 and AXIN-2, and lower cell proliferation level.Conclusions: MiR-142-3p may be involved in the development of SL and ML by interacting with CTNNB1 and AXIN-2 through Wnt signaling pathway. MiR-142-3p could serve as a potential biomarker for individualized treatment between SL and ML in the future.

Introduction Uterine leiomyoma (UL) is a common benign pelvic tumor in women that has a high recurrence rate. Our aim is to propose a prognostic index (PI) model for predicting the long-term recurrence risk of uterine leiomyoma (UL). Methods A total of 725 women who underwent myomectomy were enrolled in this retrospective multicenter study. Patients were contacted for follow-up. A PI model was proposed based on the multivariate Cox regression analysis in the model group. The predictive value of this model was tested in both internal and external validation group. Results PI formula = 1.5(if 3–5 leiomyomas) or 2(if >5 leiomyomas)+1(if residue)+1(if not submucosal)+1(if combined endometriosis). The PI value was divided into low-risk, intermediate-risk, and high-risk group by cut-off values 1.25 and 3.75. In the model group, the high-risk group had a significantly 4.55 times greater recurrence risk of UL than that in the low-risk group [cumulative recurrence rate (CR): 82.1% vs 29.5%, HR = 4.55, 95% CI 2.821–7.339]; the intermediate-risk group had a significantly 2.81 times greater recurrence risk of UL than that in the low-risk group (CR: 62.3% vs 29.5%, HR = 2.81, 95% CI 2.035–3.878). The differences between any two risk groups were also significant (P< 0.05) in both internal and external validation groups. Conclusion The model was proved to be effective in predicting recurrence of UL after myomectomy.

Background The clinical behaviors and cytogenetics of solitary uterine leiomyomas (SUL) and multiple uterine leiomyomas (MUL) vary, which greatly affects the choice of treatments for reproductive-aged patients with leiomyomas. Our previous study demonstrated that a series of microRNAs, including miR-146b-5p, are dysregulated and play important roles in the development of SUL and MUL. Long non-coding RNAs (lncRNAs) can participate in the pathogenesis of several diseases by regulating the expression of microRNAs; however, their roles in regulating miR-146b-5b and in the pathology of leiomyomas are unclear. Methods Pair-matched uterine leiomyoma and adjacent normal myometrium tissue samples were collected from 37 patients with leiomyomas, including 15 with SUL and 22 with MUL. Six paired samples (three SUL and three MUL samples) were used for lncRNAs microarray analysis. Targeted lncRNAs were selected by bioinformatics analysis, and were verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and a dual-luciferase reporter assay. Growth curve analysis and qRT-PCR were used to evaluate the effect of silencing the lncRNA lnc-AL445665.1–4 on cell proliferation and miR-146b-5p expression, respectively. Results There were 245 up-regulated and 243 down-regulated lncRNAs in SUL, and 119 up-regulated and 447 down-regulated lncRNAs in MUL. Fifty-five of the selected lncRNAs were predicted to target miR-146b-5p, which is up-regulated in SUL and down-regulated in MUL. Four lncRNAs were selected after Venn diagram analysis showing common dysregulation in the three groups. Lnc-AL445665.1–4 was selected for further exploration. qRT-PCR showed that lnc-AL445665.1–4 expression was significantly up-regulated in MUL compared with SUL in an additional 12 and 19 paired SUL-normal and MUL-normal samples, respectively. The dual-luciferase reporter assay demonstrated the presence of binding sites on lnc-AL445665.1 for miR-146b-5p. Silencing lnc-AL445665.1–4 not only inhibited cell proliferation but also negatively regulated the expression of miR-146b-5p. Conclusions Our results suggest that lnc-AL445665.1–4 may be involved in the development of MUL by interacting with miR-146b-5p. Further investigation of the roles of lncRNAs and miRNAs may help to optimize the clinical management of leiomyoma patients. Lnc-AL445665.1–4 could be a novel target for genetic therapy or serve as a biomarker for predicting the recurrence of MUL in patients that have undergone myomectomy. Electronic supplementary material The online version of this article (10.1186/s12885-019-5775-1) contains supplementary material, which is available to authorized users.

Background Several previous studies have confirmed that thrombocytosis was related to reduced survival in many solid tumors. However, the prognostic significance of thrombocytosis in endometrial carcinoma (EC) was still controversy. Therefore, we conducted this study to assess the prognostic value of thrombocytosis in EC. Methods The database including PubMed, MEDLINE, EMBASE, and Web of Science was searched to explore available literature. Above all, the hazard ratio (HR), odds ratios (OR) with 95% confidence intervals (CIs) was used to investigate the correlation between thrombocytosis and overall survival (OS) and disease-free survival (DFS). Moreover, the association between thrombocytosis and patient clinicopathological characteristics was explored. Publication bias and sensitivity analysis also were conducted in this study. Results Overall, 11 studies involving 3439 patients were contained in this study. The results revealed that pretreatment thrombocytosis was significantly related to a decreased OS (pooled HR = 2.99; 95% CI = 2.35–3.8; P

The study aimed to investigate the prognostic value of the systemic immune-inflammation index (SII) in patients with epithelial ovarian cancer (EOC).A total of 553 EOC patients were retrospectively analyzed. 250 patients from West China Second University Hospital were assigned into the discovery cohort and 283 patients from The Affiliated Hospital of Southwest Medical University were assigned into the validation cohort. The correlation between SII and survival were analyzed using Cox regression analyses and Kaplan-Meier method. Prediction accuracy was evaluated with the receiver operating characteristics (ROC) curve.The high SII (≥612) was correlated with advanced FIGO stage, lymph node metastasis, and tumor recurrence. In univariate Cox regression, patients with high SII (≥612) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to low SII patients (612) in both cohorts. In multivariate Cox regression analysis, SII was an independent prognostic indicator for PFS (HR = 7.61, 95% CI 3.34-17.35, P 0.001) and OS (HR = 6.36, 95% CI 2.64-15.33, P 0.001) in the discovery cohort. These results were verified in the validation cohort.High SII was correlated with poor survival in patients with EOC. The SII was an independent prognostic factor for patients with EOC.

BACKGROUD Previous studies have reported that the levels of L1 cell adhesion molecule (L1CAM) indicate poor prognosis of patients with various solid tumors. However, the prognostic significance of L1CAM in endometrial cancer has remained controversial. Herein, we conducted a systematic review and meta-analysis to evaluate the prognostic value of L1CAM in endometrial cancer. METHODS All studies related to the association between L1CAM expression and clinical characteristics of endometrial cancer were identified by searching the PubMed, MEDLINE, EMBASE, and Web of Science databases. Primary outcomes of the meta-analysis were the hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS). Secondary outcomes were odds ratios (ORs) for clinicopathological characteristics. Publication bias and sensitivity analysis were conducted to ensure reliability of the results. RESULTS Overall, 17 studies encompassing 7146 patients were eligible for the meta-analysis. Results showed L1CAM overexpression to be significantly associated with decreased overall survival (HR = 2.87, 95% CI; 1.81-4.55, P

Background The overexpression of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway effector, was detected in a variety of cancers. However, controversies remain in published studies on the prognostic value of TAZ expression in cancer. We performed a meta-analysis to demonstrate the prognostic significance of TAZ in overall survival (OS) and its association with clinicopathologic characteristics. Methods A systematic literature search was performed by using PubMed, EMBASE, and Web of Science databases for eligible studies investigating the association between TAZ and survival. After extracting data, we used hazard ratio (HR), odds ratio (OR) and 95% confidence intervals (95% CIs) for association evaluation, I (2) for heterogeneity across studies, and Egger's test and Begg's funnel plot for publication bias assessment. Results A total of 15 studies including 2,881 patients were analyzed. Pooled results showed that a high TAZ was significantly associated with poor OS (HR =1.82, 95% CI =1.58-2.11; I (2)=33%; P=0.11). Subgroup analysis indicated significant correlation between TAZ overexpression and OS in patients stratified by ethnicity, sample size, sample source, and staining location. Furthermore, TAZ overexpression was associated with worse OS in hepatocellular carcinoma (HR =2.26, 95% CI =1.43-3.57; P=0.49) and gastrointestinal cancers (HR =2.00, 95% CI =1.54-2.58; P=0.97), but not in non-small-cell lung cancer (HR =1.71, 95% CI =0.93-3.14; P=0.08). TAZ overexpression was also found to be significantly associated with some clinicopathologic characteristics, including TNM stage (OR =2.56, 95% CI =1.60-4.11; P=0.52), tumor differentiation (OR =3.08, 95% CI =1.25-7.63; P=0.01), and lymph node metastasis (OR =2.53, 95% CI =1.81-3.53; P=0.58). Conclusion TAZ overexpression is not only a predictive factor of poor prognosis but also associated with advanced TNM stage, poor tumor differentiation, and lymph node metastasis.

Juntao Feng,1 Jinhai Gou,1 Jia Jia,1 Tao Yi,2 Tao Cui,1 Zhengyu Li1,2 1Department of Gynecology and Obstetrics, 2Sichuan Key Laboratory of Gynecologic Oncology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex. Keywords: YAP, CCN2, ovarian cancer, verteporfin, Hippo pathway

Human leukocyte antigen (HLA)-F, a non-classical HLA-class I molecule, has attracted attention as an important immunosuppressive molecule in recent years, although the clinical relevance of HLA-F expression in cancer patients remains unclear. In the present study, HLA-F expression in 90 primary hepatocellular carcinoma (HCC) lesions and 55 corresponding adjacent normal liver tissues was analyzed by immunohistochemistry, and the associations between HLA-F expression and clinicopathological parameters and patient survival times were analyzed. Positive HLA-F expression was observed in 47.8% (43/90) of the HCC lesions and in 10.9% (6/55) of the normal liver tissues. HLA-F expression in HCC lesions was significantly correlated with patient gender (P=0.02), and venous or lymphatic invasion (P=0.02). Patients who were HLA-F-positive had worse survival times than those who were HLA-F-negative (P=0.04). The mean overall survival times for HLA-F-negative and -positive patients were 44.2 months [95% confidence interval (CI), 37.7–50.7] and 33.0 months (95% CI, 25.1–40.8), respectively. Multivariate analysis revealed that HLA-F was an independent prognostic factor for HCC patients with a hazard ratio of 2.1 (95% CI, 1.0–4.4). In conclusion, the present study demonstrated that HLA-F expression was associated with poor survival in HCC patients, and is correlated with tumor cell invasion and metastasis.

Paclitaxel resistance remains to be a major obstacle to the chemotherapy of endometrial cancer. Using proteomic-based approach, we used to identify cyclophilin A (CypA) as a potential therapeutic target for endometrial cancer. As a natural continuation, this study aimed to reveal the correlation between CypA and paclitaxel resistance and evaluate the possibility of CypA as a therapeutic target for reversal of resistance. Two paclitaxel-resistant endometrial cancer cell sublines HEC-1-B/TAX and AN3CA/TAX were generated, and expressions of CypA, P-gp, MRP-2 and survivin were demonstrated by Western blotting. CypA was knocked down by RNA interference, and the subsequent effects on the alteration of paclitaxel resistance were examined by MTT, flow cytometry and migratory/invasive transwell assays. MAPK kinases activities were examined by Western blotting. CypA knockdown led to significant inhibition of cell proliferation, induction of apoptosis and suppression of migratory/invasive capacity in HEC-1-B/TAX and AN3CA/TAX cells when exposed to paclitaxel. CypA knockdown led to reductions in total and phosphorylated MAPK kinases, including Akt, ERK1/2, p38 MAPK and JNK, in HEC-1-B/TAX cells. Furthermore, pretreatment with MAPK kinase inhibitors exhibited a synergistic effect in combination with CypA knockdown. These results demonstrated that CypA expression was up-regulated in paclitaxel-resistant cancer cells, and knockdown of CypA could reverse the paclitaxel resistance through, at least partly, suppression of MAPK kinase pathways, presenting a possibility of CypA serving as a therapeutic target to overcome paclitaxel resistance.

Objective The value of clinical specimens in identification of tumor biomarker is limited to the great individual variations among patients, the high complexity and dynamic range of protein components, and the possibility that the identified proteins are not produced by cancer cells but are due to secondary body defense mechanisms. Herein we developed a xenograft model system, in which human endometrial carcinoma cells formed a tumor in an immune-deficient nude mouse, to instantly detect proteins derived from cancer cells. Methods Using one-dimensional electrophoresis, liquid chromatography, and Q-TOF-MS/MS and FT-ICR-MS/MS analyses, the human-specific proteins in the serum of xenograft mouse could be identified and monitored without the great variations observed in a patient-based approach. Results We successfully identified 224 proteins, in which 175 (78.1%) were of mouse origin, and 45 (20.1%) were unable to be assigned as human or mouse origin. FRAS1 was identified as a uniquely human-originated protein. Its expression profile was then confirmed by Western blotting in serum samples from xenograft mice, and patients bearing endometrial carcinoma and healthy controls. Conclusions Although the mechanism of FRAS1 derivation by cancer cells remains to be illustrated, our results suggest that the xenograft model presented here should be a promising tool in the discovery of tumor biomarkers.

Herein we present a novel molecular mechanism of the antitumor effects of live-attenuated measles virus (MV) vaccine in ovarian cancer. Using a 2-DE/MS-based comparative proteomics strategy, we identified 17 proteins differentially expressed in live-attenuated MV vaccine-treated SKOV-3 ovarian cancer cells, including oxidative stress-associated enzymes and cell contact-related proteins, which indicated that live-attenuated MV vaccine could induce aberrant ROS activation. It further mediated epigenetic silencing of E-cadherin via upregulating DNMT3a that conferred both cell-cell and cell-matrix contact loss and apoptosis of ovarian cancer cells. This process could be reversed through ROS inhibition. Our study lays the theoretical foundation for the clinical application of live-attenuated MV vaccine as a potential oncotherapeutic agent for ovarian cancer treatment.

Instruction: We used proteomic approaches to identify altered expressed proteins in endometrial carcinoma, with the aim of discovering potential biomarkers or therapeutic targets for endometrial carcinoma. Methods: The global proteins extracted from endometrial carcinoma and normal endometrial tissues were separated by 2-dimensional electrophoresis and analyzed with PDQuest (Bio-Rad, Hercules, Calif) software. The differentially expressed spots were identified by mass spectrometry and searched against NCBInr protein database. Those proteins with potential roles were confirmed by Western blotting and immunohistochemical assays. Results: Ninety-nine proteins were identified by mass spectrometry, and a cluster diagram analysis indicated that these proteins were involved in metabolism, cell transformation, protein folding, translation and modification, proliferation and apoptosis, signal transduction, cytoskeleton, and so on. In confirmatory immunoblotting and immunohistochemical analyses, overexpressions of epidermal fatty acid-binding protein, calcyphosine, and cyclophilin A were also observed in endometrial carcinoma tissues, which were consistent with the proteomic results. Conclusions: Our results suggested that these identified proteins, including epidermal fatty acid-binding protein, calcyphosine, and cyclophilin A, might be of potential values in the studies of endometrial carcinogenesis or investigations of diagnostic biomarkers or treatment targets for endometrial carcinoma.

Objective: The phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in ovarian cancer cell survival and proliferation. The aim of this study was to determine whether the suppression of the PI3K catalytic subunit p110αinhibits the growth of ovarian cancer cells in vitro and in vivo. Methods: The short hairpin RNA (shRNA) was used to knock down the expression of p110α in SKOV3 human ovarian cancer cells. The effects of shRNA on cell viability and apoptosis in vitro were assessed using the MTT assay and flow-cytometric analysis. Furthermore, the growth inhibition capacity of shRNA on ovarian carcinoma xenografts was tested in nude mice. Tumor cell proliferation, apoptosis and angiogenesis were measured by proliferating cell nuclear antigen, TUNEL and CD31 immunohistochemistry, respectively. Results: Using sequence-specific shRNA, we have silenced the expression of p110α in SKOV3 cells. shRNA-mediated knockdown of p110α correlated in vitro with decreased cell viability and increased apoptosis. Furthermore, inhibition of p110α significantly delayed the growth of ovarian carcinoma xenografts, and ultimately resulted in decreased cell proliferation, induction of apoptosis as well as a reduction in microvessel density. Conclusions: Our findings suggest that shRNA-directed targeting of p110αraises the potential of its application in human ovarian cancer therapy.

With the aim to translate the discovery from proteomic research into clinical applications, we identified epidermal fatty acid-binding protein (E-FABP) and calcyphosine (CAPS) by MALDI-Q-TOF MS and validated their overexpressions by immunoblotting. Their expression statuses were examined by immunohistochemistry in 39 normal endometrium, 29 endometrial intraepithelial neoplasia (EIN) and 84 endometrial cancer (EC) cases. We evaluated the correlations to the clinicopathologic characteristics and determined whether these proteins had prognostic significance. Expressions of E-FABP and CAPS were increased 2.64- and 2.18-fold in EC by immunoblotting. Immunoreactivity of both E-FABP and CAPS were stronger in EC than in EIN or normal tissues (p < 0.001 and < 0.001). Stronger immunoreactivity of E-FABP and CAPS were shown to present with poor differentiation (p = 0.032 and 0.001), but no relevance was observed with staging (p = 1.368 and 4.306). Survival analysis indicated that immunoreactivity of CAPS was correlated to poor survival (p = 0.018), but E-FABP status appeared to be no correlation to the clinical outcome of patients (p = 0.865). Multivariate analysis indicated that CAPS might be an independent prognostic factor for survival in patients with EC (p = 0.008). Results demonstrated the ubiquitous overexpressions of E-FABP and CAPS in EC and the correlations to the clinicopathologic parameters. CAPS might be a potential prognostic factor for survival in patients with EC. The research pattern from proteomics to clinical specimens would have widespread applications.

Suberonylanilide hydroxamic acid (SAHA) is an orally administered histone deacetylase inhibitor (HDACI) that has shown significant antitumor activity in a variety of tumor cells. To evaluate if SAHA has an activity against liver cancer, and with an aim to identify the altered cellular factors upon SAHA treatment, human HepG2 cancer cell line was used as a model, and proteomic approach was utilized to elucidate the molecular mechanisms underlying SAHA's antitumor activity.Cell growth inhibition was measured by MTT method, and apoptosis was detected by means of flow cytometry analysis and TUNEL assay. Protein expression profiles were analyzed by 2-DE coupled with MALDI-Q-TOF MS/MS analysis.A total of 55 differentially expressed proteins were visualized by 2-DE and Coomassie Brilliant Blue (CBB) staining. Of these, 34 proteins were identified via MS/MS analysis. Among the identified proteins, six proteins also displayed significant expression changes at earlier time points upon SAHA treatment, and such alterations were further confirmed by semi-quantitative RT-PCR. Together, at both the mRNA and protein levels, SAHA suppressed the expression of reticulocalbin 1 precursor (RCN1), annexin A3 (ANXA3) and heat shock 27 kDa protein 1 (HSP27), while increasing the expression of aldose reductase (AR), triosephosphate isomerase 1 (TPI) and manganese superoxide dismutase (SOD2).SAHA remarkably inhibited proliferation of HepG2 cancer cells, and induced apoptosis in vitro. Using proteomics approaches, a variety of differentially expressed proteins were identified in HepG2 cancer cells before and after treatment with SAHA. This study will enable a better understanding of the molecular mechanisms underlying SAHA-mediated antitumor effects at the protein level.

Objective CypA had been identified as a potential therapeutic target to endometrial cancer in our previous research. Herein, we aimed to further elucidate the underlying comprehensive mechanisms of CypA knockdown-associated anticancer effects by cDNA microarray-based approach. Methods LV-shCypA was constructed and transfected into HEC-1-B cells. The efficiency of CypA knockdown was determined by qRT-PCR and Western blotting. The migratory/invasive capacity was examined by transwell assay. CypA knockdown-induced comprehensive gene expression alterations were analyzed using NimbleGen Human Gene Expression Microarray consisting of 45,033 probes for human genes. Functional analysis of the microarray data was performed using KEGG and Gene Ontology analyses. The selected differentially expressed genes were validated by qRT-PCR. Results Knockdown of CypA by LV-shCypA led to a significant decrease of migratory/invasive cell proportions in HEC-1-B cells. Microarray analysis showed 3533 and 2772 genes to be up-regulated and down-regulated in CypA-knockdown cells, respectively. Functional analysis showed 50 up-regulated pathways and 14 down-regulated pathways in CypA-knockdown cells, and focal adhesion signaling was one of the most enriched down-regulated pathways. The expression patterns of 16 genes in focal adhesion signaling, which encoded MAPK kinases, focal adhesion kinase (FAK), integrin subunits and laminin subunits, were validated by qRT-PCR and the consistency percentage with microarray data reached 100%. Conclusions Suppression of migratory/invasive capacity by CypA knockdown is likely associated with the down-regulation of focal adhesion signaling, which may contribute to the understanding of the role of CypA as a potential therapeutic target for endometrial cancer.

Doxorubicin (Dox) is one of the most commonly used and highly effective antineoplastic agents, but the clinical application of this broad spectrum drug is largely hampered by its poor stability and serious toxicity to normal tissues. Hence, it is essential to improve the therapeutic effect and decrease the systematic toxicity for the administration of doxorubicin. In our study, doxorubicin was incorporated into monomethoxy poly(ethylene glycol)-poly(e-caprolactone) (MPEG-PCL) micelle by a self-assembly method. The cytotoxicity and cellular uptake efficiency of Dox-loaded MPEG-PCL (Dox/MPEG-PCL) micelle against B16-F10 murine melanoma cells was examined by the methylthiazoltetrazolium (MTT) test and flow cytometry. The antitumor activity of Dox/MPEG-PCL was evaluated in C57BL/6 mice injected subcutaneously with B16-F10 cells. Toxicity was evaluated in tumor-free mice. Meanwhile, tumor proliferation, intratumoal angiogenesis and apoptotic cells were evaluated by PCNA, CD31 staining and TUNEL assay, respectively. Encapsulation of doxorubicin in MPEG-PCL micelle improved the cytotoxicity of doxorubicin and enhanced its cellular uptake on B16-F10 cell in vitro. Administration of Dox/MPEG-PCL micelle resulted in significant inhibition (75% maximum inhibition relative to controls) in the growth of B16-F10 tumor xenografts and prolonged the survival of the treated mice (P

Ovarian cancer is one of the most lethal gynecologic neoplasms. Even though various new chemotherapeutics have been developed for the treatment of ovarian cancer, drug resistance and undesired serious side effects remain unavoidable obstacles for chemotherapeutic approaches. New strategies to overcome the therapeutic dilemma are needed. Claudin-3 (CLDN3) is a recently discovered gene generally overexpressed in human ovarian cancers but not in normal ovarian tissue. Its high expression has been identified to associate with the invasion, proliferation and survival of cancer cells, making it a promising target for gene therapy of ovarian cancer. However, in gene therapy, traditional gene carriers such as virus or cationic liposomes suffer from distressing shortcomings of potential carcinogenicity, obvious cytotoxicity and immunogenicity. Nanoparticles (NPs) based on PLGA are a novel gene delivery system with good biodegradability, excellent biocompatibility and low toxcity for in vivo gene delivery compared with traditional gene carriers. We constructed a plasmid expressing shRNA targeted CLDN3 (pshCLDN3) encapsulated with PLGA-NPs, and administered it by i.p. injection to nude mice bearing intraperitoneal SKOV3 ovarian cancer, to investigate the antitumor potential of knocking down CLDN3. After 12 times of administration, the tumors of each group were compared. The underlying antitumor mechanisms were revealed by immunostaining of CD31, Ki-67 and TUNEL assay, to exhibit possible alterations in microvessel density, cell proliferation and cell apoptosis. Our study demonstrated that i.p. administration of pshCLDN3 effectively suppressed the expression of CLDN3 and, thus, inhibited the growth of ovarian tumors, significantly reducing tumor weight by 67.4% compared with blank controls (p

Lymphatic metastasis plays a critical role in ovarian cancer, indicates poor prognoses and correlates to the majority of cancer deaths. Camptothecin derivatives exhibit promising activity for the treatment of solid tumors because of its specific inhibition of eukaryotic DNA topoisomerase I. Yet, its application is hindered due to extreme water insolubility and severe side effects. It is essential to establish an efficient and safe protocol for the administration of camptothecin versus tumor metastasis and growth. In the current research, we encapsulated camptothecin with N-trimethyl chitosan (CPT-TMC) to increase its water-solubility and lower its side effects, and tested it on a high potential lymphogenous metastatic model of human ovarian cancer. In the prophase study, we successfully transfected SKOV3 cells with VEGF-D recombinant plasmid DNA (pcDNA3.1(+)/VEGF-D) to construct a cell line named SKOV3/VEGF-D and establish a feasible lymphogenous metastatic model. The antitumor and antimetastatic activities of CPT-TMC were evaluated in nude mice subcutaneously inoculated with SKOV3/VEGF-D cells at the left hindlimb claw pad. The tumor-bearing mice were divided randomly into four groups and treated twice per week for three weeks. Evan's Blue Dye was used to delineate functional lymphatic vessels. Lymphatic metastasis rates were detected by hematoxylin and eosin (HE) staining. Expression of VEGF-D and MMP-9 were investigated by immunohistochemistry. In contrast to controls, administration of CPT-TMC achieved effective inhibition in primary tumor volume and lymphogenous metastasis, yet without apparent systemic toxic effects. These effects were associated with simultaneously down-regulated VEGF-D and MMP-9 expression, significantly decreased tumor-associated lymphatic and blood sprouts, tremendously reduced systemic toxic effects, dramatically increased tumor apoptotic index. Our data indicate that CPT-TMC is superior to CPT by maximizing its anticancer and antimetastatic activities with minimal toxicity on hosts. CPT-TMC may become a potentially therapeutic strategy against human advanced ovarian cancer.

Objective: In this study, we inhibited the expression of VEGF by short hairpin RNA (shRNA) in SKOV3 ovarian cancer cells in vitro and in vivo to explore the antitumor efficacy of shRNA in ovarian cancer cells. Methods: ShRNA targeting VEGF was cloned into pGenesil-2 plasmid vector and then transfected into SKOV3 ovarian cancer cells using liposome. Silencing of VEGF expression was measured by RT-PCR and ELISA assays. Furthermore, the growth inhibition capacity of shRNA on SKOV3 intraperitoneal ovarian carcinomatosis was tested in nude mice. Tumor weight was measured. Microvessel density, number of apoptotic cells and proliferation index in tumor tissues were assessed by CD31, TUNEL and PCNA immunostaining. Results: shRNA targeting VEGF significantly silenced VEGF expression in SKOV3 ovarian cancer cells, confirmed by RT-PCR and ELISA assays (p < 0.05). In vivo, the shRNA reduced tumor weight by ∼60.3% compared with control groups (p < 0.05), accompanied with angiogenesis inhibition (p < 0.01) and apoptosis induction (p < 0.01). Conclusion: Our data indicated that shRNA-mediated silencing of VEGF might be a promising therapeutic strategy against ovarian cancer by reducing angiogenesis and inducing apoptosis.

Background Camptothecin (CPT) has recently attracted increasing attention as a promising anticancer agent for a variety of tumors. But the clinical application is largely hampered by its extreme water insolubility and unpredictable side effect. It is essential to establish an efficient and safe protocol for the administration of CPT versus melanoma. Methods Camptothecin was encapsulated with N-trimethyl chitosan (CPT-TMC) through microprecipitation and sonication. Its inhibition effect on B16-F10 cell proliferation and induction of apoptosis was evaluated by MTT assay and flow cytometric analysis in vitro. The anti-tumor activity of CPT-TMC was evaluated in C57BL/6 mice bearing B16-F10 melanoma. Tumor volume, tumor weight and survival time were recorded. Assessment of apoptotic cells within tumor tissue was performed by TUNEL assay. Antiangiogenesis and antiproliferation effects of CPT-TMC in vivo were conducted via CD31 and PCNA immunohistochemistry, respectively. Results CPT-TMC efficiently inhibited B16-F10 cells proliferation and increased apoptosis in vitro. Experiment group showed significant inhibition compared with free CPT-treated group (81.3% vs. 56.9%) in the growth of B16-F10 melanoma xenografts and prolonged the survival time of the treated mice (P < 0.05). Decreased cell proliferation, increased tumor apoptosis as well as a reduction in angiogenesis were observed. Conclusions Our data suggest that N-trimethyl chitosan-encapsulated camptothecin is superior to free CPT by overcoming its insolubility and finally raises the potential of its application in melanoma therapy.