Prognosis Of Ovarian Cancer Patients Research Articles

Developing Ovarian Cancer Sensors Using Molecular Perceptron

Ovarian cancer patient prognosis and quality of life are significantly affected by the failure to accurately diagnose disease at early stage. Currently, less than 15% of ovarian cancer patients are diagnosed at stage 1, when 5-year survival rates are near 93%. Early detection may save more than 80% of women diagnosed with ovarian cancer. Our goal is to develop long-term implantable carbon nanotube-based sensors for ovarian cancer biomarkers to transiently detect and monitor their levels in patients. The proposed sensors will harness the unique optical properties and sensitivity of single-walled carbon nanotubes. To improve sensitivity and specificity of such sensors, previously developed to detect ovarian cancer biomarkers in vivo, we used molecular perceptron—data analytics-based methods to detect specific spectroscopic fingerprints from the binding of protein biomarkers to the nanotube surface.

Prognostic Values of Transforming Growth Factor-Beta Subtypes in Ovarian Cancer.

Purpose To explore the potential role of the transforming growth factor-beta (TGF-β) subtypes in the prognosis of ovarian cancer patients. Materials and Methods. The prognostic roles of individual TGF-β subtypes in women with ovarian cancer were retrieved from the Kaplan-Meier plotter (KM plotter) database. In addition, the Oncomine database and immunohistochemistry were used to observe the mRNA and protein expression of TGF-β subtypes between human ovarian carcinoma and normal ovarian samples, respectively. Results TGF-β1 and TGF-β4 were totally uncorrelated with survival outcomes in women with ovarian cancer. Increased TGF-β2 and TGF-β3 mRNA expression was markedly related to unfavorable prognosis, especially in women with serous, poorly differentiated, and late-stage ovarian carcinoma. High expression levels of TGF-β2 were related to worse progression-free survival (PFS) while TGF-β3 was linked to unfavorable overall survival (OS) and PFS in women with TP53-mutated ovarian cancer. TGF-β2 was associated with poor OS and PFS from treatment with chemotherapy with platins, Taxol, or a platin+Taxol. However, overexpression of TGF-β3 was associated with poor OS from the use of platins and poor PFS of Taxol or a platin+Taxol in women with ovarian carcinoma. Furthermore, the expression of TGF-β2 mRNA and protein was higher but only TGF-β3 mRNA expression was higher in cancerous tissues than in normal ovarian samples. Conclusion Higher expression of TGF-β2 functioned as a significant predictor of poor prognosis in women with ovarian cancer, especially those with TP53 mutations or who were undergoing chemotherapy with platins, Taxol, or a platin+Taxol.

MicroRNA-489 targets XIAP to inhibit the biological progression of ovarian cancer via regulating PI3K/Akt signaling pathway and epithelial-to-mesenchymal transition.

Ovarian cancer (OC) is a deathful malignant tumor in women worldwide, and its poor prognosis mainly results from metastasis. Recently, microRNA (miRNA/miR) has been found to exert crucial functions in the progression of multiple tumors by affecting expressions of their targets. However, the biological roles and the potential mechanism of miR-489 in OC need further elucidation. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was utilized to confirm the miR-489 expressions in OC tissue samples and cell lines. The functions of miR-489 were analyzed by performing functional assays, such as MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays and transwell assays. The downstream target of miR-489 was confirmed by TargetScan and luciferase reporter assay. Western blot was conducted to detect the expression of indicators associated with the down-stream signaling pathway. MiR-489 was prominently downregulated in OC tissues and cells, and the decreased miR-489 expression was related to malignant clinicopathologic features and poor prognosis of OC patients. Functional assays demonstrated that miR-489 could suppress OC cell viability, invasion, and migration. X-linked inhibitor of apoptosis protein (XIAP) was identified as a target of miR-489 and partially regulated the functions of miR-489 in OC. Moreover, we found that miR-489 inhibits OC progression via regulating phosphatidyl-inositol 3-kinase/protein kinase B pathway (PI3K/AKT) and epithelial-to-mesenchymal transition (EMT). Our results demonstrated that miR-489 inhibited OC development by directly binding to XIAP and regulating PI3K/Akt and EMT signal pathways, and miR-489 might serve as a promising biomarker for OC treatment in the future.

Low expression of NCALD is associated with chemotherapy resistance and poor prognosis in epithelial ovarian cancer

BackgroundLow expression of NCALD(neurocalcin delta) in peripheral blood of ovarian cancer patients predicts poor prognosis. However, the molecular mechanism of NCALD in ovarian cancer and its relationship with chemotherapy outcomes is unclear. The aim of this study was to investigate the potential signaling pathways of NCALD and to evaluate its ability to predict chemotherapy outcomes and prognosis.MethodsHigh-throughput RNA sequencing data were downloaded from TCGA. GSEA explored the potential signaling pathways of NCALD. The expression of NCALD in chemotherapy sensitive and chemotherapy resistant ovarian cancer patients was detected by TCGA data and clinical samples. ROC analysis confirmed the ability of NCALD to predict chemotherapy outcomes. The association between NCALD expression and prognosis in ovarian cancer patients was assessed using Kaplan-Meier plotter.ResultsIn patients with NCALD overexpression, genes expression related to ERK1 / 2 signaling pathway, NF-kappaB signaling pathway, TGF-β signaling pathway and immune response pathway was increased, especially ERK1 / 2 signaling pathway. The expression of NCALD in chemoresistant patients was significantly lower than chemosensitive patients. In TCGA data and immunohistochemical samples, the AUC of NCALD expression predicting chemotherapy outcome was 0.59 and 0.64, respectively. In clinical samples, low expression of NCALD was associated with poor OS and PFS.ConclusionsNCALD may activate the ERK1 / 2 signaling pathway in ovarian cancer. As a new biomarker of chemotherapy sensitivity, NCALD was significantly down-regulated in chemotherapy resistance ovarian cancer patients. Low expression of NCALD in ovarian cancer is associated with poor OS and PFS. In the future, further research will be needed on the potential mechanism and clinical application value of NCALD in ovarian cancer.

ARTICLE WITHDRAWN] Long Noncoding RNA KCNQ1OT1 Accelerates the Progression of Ovarian Cancer via MicroRNA-212-3/LCN2 Axis.

Long noncoding RNA KCNQ1OT1 (KCNQ1OT1) has been identified to be deregulated in several kinds of cancers. However, its expression pattern and functions in ovarian cancer remain unknown. Bioinformatics analysis showed that miR-212-3p, an identified suppressor in ovarian cancer, was a direct target of KCNQ1OT1, suggesting that KCNQ1OT1 may play a role in ovarian cancer progression via targeting miR-212-3p. Here we aimed to explore the effect of KCNQ1OT1 on the carcinogenesis of ovarian cancer, as well as to investigate miR-212-3p roles in this process. The expression of KCNQ1OT1 and miR-212-3p in ovarian cancer tissues and cells was detected by qPCR. MTT, flow cytometry, wound healing, Transwell chambers, and in vivo tumor formation assays were carried out to assess cell proliferation, apoptosis, migration, invasion, and tumorigenesis, respectively. RNA pulldown and luciferase gene reporter assays were used to evaluate the RNA–RNA interaction. The results showed that KCNQ1OT1 was overexpressed in ovarian cancer tissues and cells, which closely associated with the advanced clinic process and poor prognosis in ovarian cancer patients. Upregulation of KCNQ1OT1 significantly enhanced cell growth, migration, and invasion and inhibited cell apoptosis via miR-212-3p. In addition, we identified that lipocalin2 (LCN2) was a direct target of miR-212-3p and functioned as an oncogene to promote cell growth and to inhibit cell apoptosis. Furthermore, we observed that KCNQ1OT1 overexpression significantly enhanced the tumorigenesis of SKOV3 cells, whereas this effect was significantly impaired when LCN2 expression was downregulated. Overall, the present study reveals that KCNQ1OT1 functions as an oncogene in ovarian cancer via targeting miR-212-3p/LCN2 axis, which might provide new markers and targets for ovarian cancer diagnosis and treatment.

Clinical Interest of Combining Transcriptomic and Genomic Signatures in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer is one of the deadliest gynecological malignancies and remains a clinical challenge. There is a critical need to effectively define patient stratification in a clinical setting. In this study, we address this question and determine the optimal number of molecular subgroups for ovarian cancer patients. By studying several independent patient cohorts, we observed that classifying high-grade serous ovarian tumors into four molecular subgroups using a transcriptomic-based approach did not reproducibly predict patient survival. In contrast, classifying these tumors into only two molecular subgroups, fibrosis and non-fibrosis, could reliably inform on patient survival. In addition, we found complementarity between transcriptomic data and the genomic signature for homologous recombination deficiency (HRD) that helped in defining prognosis of ovarian cancer patients. We also established that the transcriptomic and genomic signatures underlined independent biological processes and defined four different risk populations. Thus, combining genomic and transcriptomic information appears as the most appropriate stratification method to reliably subgroup high-grade serous ovarian cancer patients. This method can easily be transferred into the clinical setting.

MicroRNA-488 inhibits ovarian cancer cell metastasis through regulating CCNG1 and p53 expression.

The roles of microRNAs (miRNAs) have been widely exploited in cancer. MiRNAs have become a potential breakthrough in cancer diagnosis and treatment. Here, the regulatory mechanism of microRNA-488 (miR-488) was investigated in ovarian cancer (OC). The expression levels of miR-488 and CCNG1 (Cyclin G1) were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot assays. Transwell assay and epithelial-mesenchymal transition (EMT) markers were used to clarify the effect of miR-488 on cell metastasis. The dual-luciferase reporter assay was used to verify the relation between miR-488 and CCNG1. The expression of miR-488 was reduced in OC, which was associated with poor clinical outcomes and prognosis in OC patients. MiR-488 inhibited cell metastasis in OC by blocking EMT and promoting tumor suppressor p53 expression. In addition, CCNG1 was confirmed as a direct target of miR-488. Upregulation of CCNG1 impaired the inhibitory effect of miR-488 in OC. MiR-488 serves as a tumor inhibitor in OC by suppressing cell metastasis, indicating that miR-488 has a great potential in the diagnosis and treatment of OC.

High Expression of RING Finger Protein 126 Predicts Unfavorable Prognosis of Epithelial Ovarian Cancer.

BackgroundOvarian cancer (OC) is one of the leading causes of cancer-related mortality worldwide. The clinical outcome of EOC remains unsatisfactory with current therapeutic approaches such as surgery and platinum/taxane-based chemotherapy. Therefore, novel prognostic markers and personalized therapies targeting specific molecules are urgently needed. Here, we explored whether RNF126, an E3 ubiquitin ligase, is a potential biomarker for epithelial ovarian cancer (EOC).Material/MethodsThis was a retrospective cohort study of 122 EOC patients. The chi-square test was used to assess correlations between RNF126 level and clinical characteristics of enrolled patients. Univariate and multivariate analyses were performed to monitor the prognosis of enrolled patients. In addition, proliferation and invasion assays were conducted to assess the cellular effects of RNF126 on SKOV3 cell progression.ResultsImmunohistochemistry analysis (IHC) revealed that RNF126 was upregulated in EOC tissues compared to adjacent ovarian tissues. In addition, RNF126 expression was remarkably associated with LN metastasis, pathological differentiation, and FIGO stage. RNF126 protein level was found to be an independent biomarker for predication of prognosis in ovarian cancer patients. Cellular results showed that RNF126 enhanced the proliferation and invasion abilities of SKOV3 cells.ConclusionsUpregulated protein level of RNF126 in EOC tissues is a biomarker predicting poor outcomes of EOC patients.

Diagnostic significance of serum miR-26b and miR-21 expressions in ovarian cancer and their associations with clinicopathological characteristics and prognosis of patients.

The aim of this study was to detect the expressions of serum micro-ribonucleic acid (miR)-26b and miR-21 in ovarian cancer patients, and to explore their associations with the diagnosis, clinicopathological parameters and prognosis of ovarian cancer. A total of 86 patients diagnosed with ovarian cancer in our hospital from January 2014 to January 2015 were enrolled in the observation group. Meanwhile, another 86 subjects receiving physical examination in our hospital during the same period were enrolled in the control group. The expressions of serum miR-26b and miR-21 in both groups were detected via Real Time fluorescence-quantitative Polymerase Chain Reaction (RT-qPCR). Receiver operating characteristic (ROC) curves were plotted. Later, the clinical diagnostic value of combined detection of miR-26b and miR-21 in ovarian cancer was analyzed. Moreover, the associations of serum miR-26b and miR-21 expressions with clinicopathological characteristics and prognosis of ovarian cancer patients were explored. The expression of serum miR-26b in ovarian cancer patients was significantly lower than that of healthy subjects, while miR-21 expression was markedly higher in ovarian cancer patients (p<0.05). The area under the ROC curve (AUC), the sensitivity and specificity of miR-26b detection, miR-21 detection and combined detection in the diagnosis of ovarian cancer were 0.753 vs. 0.826 vs. 0.916, 47.2 vs. 76.3 vs. 87.6 and 78.5 vs. 85.6 vs. 90.4, respectively. Therefore, it could be observed that both the sensitivity and specificity of combined detection were remarkably higher than those of single detection (p<0.05). In addition, the expressions of serum miR-26b and miR-21 were associated with clinical stage and lymph node metastasis of ovarian cancer patients, whereas it was not correlated with age and histological type. The 3-year survival rate of patients with high expression of serum miR-26b was significantly higher than that in those with low expression of serum miR-26b. However, the 3-year survival rate of patients with low expression of serum miR-21 was higher than that in those with high expression. MiR-21 is highly expressed, while miR-26b is lowly expressed in the serum of ovarian cancer patients. Both of them may be involved in the incidence and development of ovarian cancer. Furthermore, combined monitoring of serum miR-26b and miR-21 has a certain value in the clinical diagnosis and treatment of ovarian cancer.

Clinical significance of PI3 and HLA-DOB as potential prognostic predicators for ovarian cancer.

BackgroundThe outcomes of ovarian cancer patients are very poor, therefore it is necessary to find prognostic biomarkers and explore the potential underlying molecular mechanisms of ovarian cancer.MethodsIn this study, a gene expression microarray data set covering 562 ovarian serous cystadenocarcinomas and 12,042 genes was downloaded from The Cancer Genome Atlas (TCGA) database. For each candidate gene, samples were allocated into a “high group” or a “low group” according to the expression level. The overall survival (OS) rates were compared between the two groups. Then, a univariate analysis and a multivariate Cox proportional hazards test were carried out to examine the associations between genes and multiple clinicopathological parameters.ResultsAmong all candidate genes, PI3 (peptidase inhibitor 3, often called elafin) and HLA-DOB (major histocompatibility complex, class II, DO beta) were identified as hub genes. PI3 (P=7.99e-7) and HLA-DOB (P=7.52e-6) showed significant associations with OS, especially in patients with stage III or IV disease. Both PI3 (HR =1.84, P=3.77e-7) and HLA-DOB (HR =0.68, P=0.001134) were identified as independent predictors of ovarian cancer patients OS. In addition, IRF1 (interferon regulatory factor 1) (P=1.16e-15) and SPI1 (Spi-1 proto-oncogene) (P=2.03e-6) were identified as the most significant transcription factors.ConclusionsOur data indicate that PI3 and HLA-DOB are potential biomarkers that could be used to predict the prognosis of ovarian cancer patients, and may play important roles in ovarian cancer progression. Further experimental and clinical studies with larger sample sizes are needed to confirm these findings.

High expression of STAT2 in ovarian cancer and its effect on metastasis of ovarian cancer cells

To investigate the expression of signal transduction and activator of transcription 2 (STAT2) in ovarian cancer and its correlation with the prognosis of ovarian cancer patients and explore the role of STAT2 inregulating metastasis of ovarian cancer cells. RT-qPCR was performed to detect the expression of STAT2 mRNA in 62 fresh frozen ovarian cancer tissues and 62 normal ovarian tissues; immunohistochemistry was used to detect STAT2 protein expressions in 95 paraffin-embedded ovarian cancer samples and 33 normal ovarian tissues. Kaplan-Meier method was used to analyze the correlation between the expression of STAT2 and the prognosis of the patients. We also examined the relationship between STAT2 and the patients' prognosis by analyzing the data in Kaplan-Meier Plotter database. Western blotting was performed to detect the expression of STAT2 in different ovarian cancer cell lines. In A2780 cells with the highest STAT2 expression, we examined the effects of STAT2 interference on cell migration and invasiveness using Transwell migration assay and on the expressions of the downstream molecule epidermal growth factor receptor (EGFR). Ovarian cancer tissues expressed significantly higher levels of STAT2 mRNA than normal ovarian tissue. A high STAT2 mRNA expression was correlated with an advanced FIGO stage. Immunohistochemistry showed that 67.4% of the ovarian cancer samples, as compared with 28.3% of normal ovarian tissues, showed high STAT2 expressions. In ovarian cancer patients, a high expression of STAT2 protein was associated with ascites volume, distant metastasis and FIGO stage (P < 0.05). Survival analysis showed that ovarian cancer patients with a high expression of STAT2 protein had poor overall survival (P=0.021) and progression-free survival (P=0.018). STAT2 was overexpressed in all the ovarian cancer cell lines tested, and A2780 cell lines showed the highest expression. Interference of STAT2 significantly suppressed the migration and invasiveness (P < 0.01) and lowered the expression level of EGFR in A2780 cells. STAT2 is overexpressed in ovarian cancer. A high expression of STAT2 is associated with a poor prognosis of ovarian cancer patients. STAT2 may promote the metastasis of ovarian cancer by enhancing the expression of EGFR.

The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.

N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

Loss of hnRNPA2B1 inhibits malignant capability and promotes apoptosis via down-regulating Lin28B expression in ovarian cancer.

Ovarian cancer has the highest mortality rate among all gynecological cancers with its pathogenic mechanisms largely unknown. Here, we uncovered that ovarian cancer tissues exhibit higher heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) expression than normal ovarian epithelium tissues. Increased hnRNPA2B1 level matches along with poor prognosis of ovarian cancer patients. Importantly, hnRNPA2B1 inhibition hampers growth, reduces mobility of ovarian cancer cells in vitro and hinders xenograft tumor formation in vivo. Transcriptome profiling analysis reveals that hnRNPA2B1 dictates the expression of various important genes involved in tumorigenesis and Lin-28 Homolog B (Lin28B) is down-regulated upon hnRNPA2B1 loss. hnRNPA2B1 regulates expression of Lin28B via binding to Lin28B mRNA and enhancing its stability. Furthermore, knockdown of Lin28B reduces proliferation and mobility of ovarian cancer cells and impairs tumorigenesis in vivo, whereas Lin28B overexpression promotes xenograft tumor formation. Finally, re-expression of Lin28B in hnRNPA2B1 knockdown cells results in rescued phenotypes. Collectively, our results demonstrate that hnRNPA2B1 facilitates the malignant phenotype of ovarian cancer through activating Lin28B expression.

Expression of PD-L1 in ovarian cancer and its synergistic antitumor effect with PARP inhibitor

BackgroundOvarian cancer samples were studied to determine the expression of programmed death ligand-1 (PD-L1) and its relationship with prognosis, and to explore the effect and potential mechanism of a PARP inhibitor combined with PD-L1 monoclonal antibody for the treatment of ovarian cancer. Materials and methodsPD-L1 expression in paraffin-embedded tissues of ovarian cancer was detected by immunohistochemistry (IHC). Flow cytometry was used to detect PD-L1 expression in TILs. Furthermore, we investigated the mechanism of the upregulation of PD-L1 expression by PARP inhibitors in vitro and verified the combined effect in vivo. ResultsOur study demonstrated that PD-L1 expression in ovarian cancer tissues was associated with the FIGO stage (P = 0.026). OS was significantly lower in high PD-L1 expression group than in the low expression group (P = 0.0005, HR = 2.689), PD-L1 high expression (P = 0.023, HR = 2.275) and FIGO stage (P = 0.024, HR = 11.229) were independent risk factors affecting the survival and prognosis of ovarian cancer patients. Flow cytometry test suggested that PD-L1+ expression was negatively correlated with CD8+ T cell count in ovarian cancer cells (P = 0.054, r = −0.624). In vitro experiments revealed that PD-L1 expression of ovarian cancer cell lines was upregulated after intervention with PARP inhibitors through the Chk1 pathway. The results of in vivo experiments suggested that the growth volume and quality of tumors in the combination group were significantly lower than those in control group (P < 0.05). ConclusionsPARP inhibitors could induce upregulation of PD-L1 expression by promoting phosphorylation of chk1. Antagonistic PD-L1 could reverse the inhibitory effect of PARP inhibitors on CD8+T cells, and had synergistic antitumor effect with PARP inhibitors.

Histotype-specific analysis of acid ceramidase expression in ovarian cancer.

Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller sample sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (P = 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.

Low EIF2B5 expression predicts poor prognosis in ovarian cancer.

Ovarian cancer has the highest mortality among gynecological cancers. Although ovarian cancer usually responds well to chemotherapy, most patients still have a poor prognosis. EIF2B5 is a crucial molecule in posttranscriptional modifications involved in tumor progression, and here we investigated the prognostic role of EIF2B5 in ovarian cancer. We examined the differential expression of EIF2B5 mRNA in ovarian cancer by exploring The Cancer Genome Atlas (TCGA) database. The chi square test was used to identify a clinical correlation. Survival analysis and Cox regression model were performed to determine the association between EIF2B5 expression and overall survival (OS) in ovarian cancer patients. As a result, Low EIF2B5 expression was found in ovarian cancer tissues and correlated with survival status. Survival analysis showed that ovarian cancer patients with low EIF2B5 expression had a short OS. Moreover, Cox regression analysis indicated that low EIF2B5 expression was an independent risk factor for a poor prognosis in ovarian cancer. Additionally, according to gene set enrichment analysis, mesenchymal transition, angiogenesis, coagulation, and bile acid metabolism were differentially enriched in ovarian cancer with high EIF2B5 expression. In conclusion, Low EIF2B5 expression is an independent risk factor for a poor prognosis in ovarian cancer patients.

CXCL13, FCRLA, PLA2G2D and MS4A1&amp;nbsp;Were Identified As Prognostic Biomarkers and Correlated with Immune Infiltration in Ovarian Cancer by Integrating&amp;nbsp;TMB and Microenvironment Analysis

Background: The six most common malignancies in the world include ovarian cancer (OC), which is a severe tumor that seriously threatens women's lives. And it’s also one of the leading causes of death of patients with various gynecological tumors. Although many papers have reported that high TMB can generate many neoantigens to incited anti-tumor immune response and the immune infiltration degree of the tumor has an essential influence on prognosis, the interrelationship between TMB and immune scores in OC and its effect on prognosis were not examined systematically. Under this circumstance, our current study aims to discover the novel biomarkers in OC, and seek to investigate the role of hub genes in OC. Results: We divided OC cases into two groups: the low tumor mutational burden (TMB) group and the high TMB group hinged on the somatic mutation data from the Cancer Genome Atlas (TCGA). Our researches found that the higher TMB, the better the survival prognosis of ovarian cancer. And we also categorized OC cases into low immune scores group and high immune scores group based on ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm from TCGA. It’s shown that the B cells naive, macrophages M0, and dendritic cells activated tended to be down-regulated in the low immune scores group, and the T cells CD8, T cells CD4 memory activated, and macrophages M2 tended to be up-regulated in the high immune scores group. To better explain the effects of TMB and the genes involved in immune cells on prognosis, we filtrated differential expression genes (DEGs) whose expression considerably linked to prognosis in OC patients. In addition, we analyzed Up-DGEs (Up-regulated DEGs) and Down-DEGs (Down-regulated DEGs) and then screened the top ten small-molecule drugs in CMap (ConnectivityMap), six candidate small molecule drugs were identified that are closely related to the clinical treatment of OC. Meanwhile, our researches further demonstrated that Up-DEGs were mainly involved in immune response and T cell proliferation by functional enrichment analysis and protein‐protein interaction (PPI) network. Finally, we validated these genes from the Group on Earth Observations (GEO) which included CXCL13, FCRLA, PLA2G2D and MS4A1. Funding Statement: Contributions received from the TCGA network, the GTEx network and the CCLE Network. This study was supported by grants from the National Natural Science Foundation of China (No. 81572900). The Fundamental Research Funds for the Central Universities of Central South University (No. 502221804). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.

MicroRNA-149 suppresses the malignant phenotypes of ovarian cancer via downregulation of MSI2 and inhibition of PI3K/AKT pathway.

Ovarian cancer (OC) is one of the most lethal gynecologic malignant tumors. Emerging evidence has indicated that the dysregulation of microRNAs (miRNAs/miRs) participates in the OC progression. It has been revealed that miR-149 acts either as an oncogene or a tumour suppressor in various human tumors. The current study focused on the biological roles and potential mechanism of miR-149 in OC. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine the level of miR-149 expression in 72 pairs of OC tissues and para-cancerous specimens. We further measured the miR-149 levels in OC cells. As we indicated that miR-149 inhibited OC cell viability, we further explored the roles of miR-149 in OC cell invasion and migration by performing the transwell assays. As we suggested that MSI2 was one target for miR-149 in OC cell lines, the expressions and clinical significance of MSI2 in OC were further investigated. We first detected miR-149 expressions in the OC tissues using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and the data showed that miR-149 was dramatically downregulated in the OC tissue samples in comparison to matched normal tissue samples. Additionally, the downregulation of miR-149 in OC was found to be related to the poor prognosis and malignant clinicopathologic characteristics of patients with OC. MiR-149 overexpression significantly suppressed the OC cell proliferation, invasion, and migration as determined by functional assays, including MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays and transwell assays. Furthermore, the dual-luciferase reporter assay demonstrated that MSI2 was an efficient target of miR-149 in OC cells. Finally, some findings also revealed that miR-149 exerted its biological function in OC cells via direct regulation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT). Collectively, miR-149 exerted anti-OC roles at least partially by regulating MSI2 via PI3K/AKT. The findings of this study suggested that miR-149 might be a promising target in the diagnosis and prognosis for OC patients.

The influence of polypharmacy, potentially inappropriate medications, and drug interactions on treatment completion and prognosis in older patients with ovarian cancer

BackgroundOlder patients with cancer are at increased risk of exposure to polypharmacy (PP), potential drug interactions (PDIs), and Potentially inappropriate Medications (PIMs). Objectives of this study were to describe PP, PIMs, and PDIs, and to analyse the associations with completion of 1st line chemotherapy and prognosis in ovarian cancer (OC) patients. MethodsRegistry-based study including a 10-year national cohort of patients diagnosed with epithelial OC in Denmark. Descriptive statistics, multivariate logistic regression analyses, Kaplan-Meier, and Cox regression analyses were performed to analyse the data. ResultsA total of 3795 patients were included and described. Further analyses were performed on 2219 patients registered with a date of surgery and combination chemotherapy with platinum and a taxane or platinum monotherapy. Exposure to ≥2 PDIs was associated with not completing chemotherapy, odds ratio (OR) 2.27 (1.18–4.37). Major and extensive PP were associated with increased mortality at 0–6 months after diagnosis, HR 3.15(1.59–6.22) and 5.43(2.34–12.6), respectively. PIMs were associated with increased mortality from six months after diagnosis. At 6–12 months: hazard ratio (HR) 1.50(1.06–2.11) and 2.38(1.25–4.50) with 1–2 and ≥ 3 PIMs, respectively. At 12 months: HR 2.08(1.31–3.29) with ≥3 PIMs. Age was not associated with treatment completion. ConclusionsDrug use influences treatment completion and prognosis in OC patients. A thorough review of patients' medications aiming to minimize the number of PIMs and PDIs might improve the course of these patients' disease.

MiR-21 modulates the polarization of macrophages and increases the effects of M2 macrophages on promoting the chemoresistance of ovarian cancer

AimsChemoresistance is a major underlying cause of relapse or death in ovarian cancer patients. Emerging evidence has shown that macrophages could play an essential role in mediating the chemoresistance of cancer cells. MiR-21 has been reported to be an oncogene, which promotes chemoresistance in cancer. Here, we aim to investigate the role that miR-21 plays in polarization of macrophages and ovarian cancer progression. Main methodsThe CIBERSORT algorithm was used to investigate immune cell infiltration in ovarian cancer tissues. To explore the role that miR-21 played in macrophages, M2 macrophages transfected with a miR-21 mimic or a miR-21 inhibitor were co-cultured with ovarian cancer cells. Western blotting was used to detect protein expression levels. CCK8 was used to detect the IC50 of ovarian cancer cells. Flow cytometry was used to detect apoptosis and the cell cycle of ovarian cancer cells. Key findingsIn this study, we found that higher expression of M1 macrophages and lower expression of M2 macrophages correlated with a better prognosis of ovarian cancer patients. M2 macrophages promoted the chemoresistance of ovarian cancer cells. The results showed that miR-21 could partially regulate the polarization of macrophages. Furthermore, M2 macrophages transfected with the miR-21 mimic significantly promoted chemoresistance and inhibited apoptosis of ovarian cancer cells, while the M2 macrophages transfected with the miR-21 inhibitor showed the opposite effects. SignificancemiR-21 plays an important role in regulating macrophage polarization, therefore increasing the M2 macrophage-mediated chemoresistance in ovarian cancer cells.