Poor Prognosis In Ovarian Cancer Research Articles

Vitamin D Exposure and Ovarian Cancer Risk and Prognosis.

Given the poor prognosis of ovarian cancer and limited population-level strategies for early detection and long-term treatment success, knowledge of modifiable risk factors for prevention and improved prognosis is important. Vitamin D has received wide scientific interest in cancer research as having the potential to be one such factor. We carried out a systematic narrative review of the literature on vitamin D and ovarian cancer risk and survival. We included 17 case-control and cohort studies on ovarian cancer incidence. Five analyses were of sun exposure, among which three reported an inverse association. Of 11 analyses of dietary vitamin D, two reported an inverse association. Among five studies of 25(OH)D levels, an inverse association was reported in two. Across all studies the findings were inconsistent, but some recent studies have suggested that vitamin D exposure at earlier ages may be important. Only three studies examining vitamin D exposure in relation to survival among ovarian cancer survivors were identified and the findings were inconsistent. The evidence to date supports a null influence of vitamin D on both ovarian cancer risk and survival. Future research should ensure that exposure assessment captures vitamin D exposure from all sources and for the etiologically or prognostically pertinent period.

Overexpression of PRC1 indicates a poor prognosis in ovarian cancer

Protein regulator of cytokinesis-1 (PRC1) is a microtubule-associated factor involved in cytokinesis. Recent studies have indicated that PRC1 overexpression is involved in tumorigenesis in multiple types of human cancer. However, the expression, biological functions and the prognostic significance of PRC1 in ovarian cancer have not yet been clarified. In this study, it was confirmed that the PRC1 mRNA and protein expression levels were upregulated in high-grade serous ovarian carcinoma (HGSOC) tissues, particularly in patients without breast cancer susceptibility gene (BRCA) pathogenic mutations. PRC1 overexpression contributed to drug resistance, tumor recurrence and a poor prognosis. The findings also indicated that PRC1 knockdown decreased the proliferation, metastasis and multidrug resistance of ovarian cancer cells in vitro. It was also demonstrated that forkhead box protein M1 (FOXM1) regulated the mRNA and protein expression of PRC1. Dual-luciferase reporter assay and rescue assay confirmed that PRC1 was a direct crucial downstream target of FOXM1. On the whole, the findings of this study confirmed that PRC1 was a major prognostic factor of HGSOC and a promising therapeutic biomarker for the treatment of ovarian cancer.

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.

The Prognostic Value of the Chromobox Family in Human Ovarian Cancer.

Ovarian cancer is one of the most lethal gynecologic tumors in women and has a poor prognosis. The purpose of our study was to identify new prognostic markers in ovarian cancer. We examined the prognostic roles of mRNA expression of the chromobox (CBX) family in patients with ovarian cancer utilizing the Kaplan-Meier plotter database. The prognostic values and expression levels of CBX members associated with prognosis were further evaluated using KM plotter in diverse subgroups and immunohistochemistry (IHC) analysis in ovarian carcinoma. The results revealed that elevated CBX1-3 mRNA expression may predict poor overall survival (OS) and progression-free survival (PFS) outcomes in patients with ovarian cancer. Notably, in women with ovarian cancer, increased CBX1 mRNA expression was linked to a short OS in all stages and in the grade II and grade III subgroups. Additionally, CBX2 and CBX3 were strongly related to short OS in stage III+IV patients, and a link between high CBX3 mRNA expression and unfavorable OS in grade II patients was observed. High expression levels of CBX1 and CBX3 were significantly associated with chemotherapy resistance in ovarian cancer patients. IHC staining showed that the CBX1-3 proteins were upregulated in serous ovarian carcinoma tissues compared with normal ovarian tissues. Therefore, our results indicated that CBX1-3 could be attractive biomarkers for predicting poor prognosis of ovarian cancer.

Construction of novel mRNA-miRNA-lncRNA regulatory networks associated with prognosis of ovarian cancer

Background: Ovarian cancer (OC) is the most lethal malignancy in the female reproductive system. Growing evidences demonstrates that competing endogenous RNA (ceRNA) network play crucial roles in the occurrence and progression of tumors. Therefore, we aimed to explore and identify novel mRNA-miRNA-lncRNA ceRNA networks associated with prognosis of OC.Methods: The differentially expressed gene (DEGs) of four expression profiles datasets (GSE5438, GSE40595, GSE38666 and GSE26712) were collected from Gene Expression Omnibus (GEO) database and analyzed with NetworkAnalyst. Intersection of DEGs were further employed for Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis. Protein-protein interaction (PPI) network and hub genes of DEGs were also identified. The expression levels and survival analysis of the hub genes in OC and their upstream miRNAs and lncRNAs were performed by various bioinformatics databases. More importantly, ceRNA networks were constructed based on mRNA-miRNA-lncRNA in OC.Results: A total of 178 DEGs including 38 upregulated and 140 downregulated genes from intersected DEGs of four expression profiles were identified in OC. Functional enrichment analysis suggested that the commonly DEGs were enriched in regulating enzyme inhibitor activity, glycosaminoglycan and G protein-coupled receptor binding, cell morphogenesis, and involved in pathways including metabolic process, proteoglycans in cancer. Top 10 hub genes with higher connectivity degree were selected for subsequent expression and prognosis analysis. After take expression levels and prognostic roles of hub genes and their upstream miRNAs and lncRNAs in OC into consideration, 2 mRNAs (TACC3 and CXCR4), 2 miRNAs (hsa-miR-425-5p and hsa-miR-146a-5p) and 3 lncRNAs (FUT8-AS1, LINC00665 and LINC01535) were significantly associated with the poor prognosis of OC. The mRNA-miRNA-lncRNA networks (TACC3-hsa-miR-425-5p-FUT8-AS1 and CXCR4-hsa-miR-146a-5p-LINC00665/LINC01535) were eventually constructed in OC based on ceRNA mechanism.Conclusion: We successfully constructed novel ceRNA network associated with the prognosis of ovarian cancer, which may provide a new strategy for early diagnosis and therapeutic intervention of OC.

CircCELSR1 (hsa_circ_0063809) Contributes to Paclitaxel Resistance of Ovarian Cancer Cells by Regulating FOXR2 Expression via miR-1252

Ovarian cancer is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance to chemotherapeutic drugs such as paclitaxel (PTX) occurring in the very early stage is one of the important factors of the poor prognosis of ovarian cancer. Herein, we aim to study the dysregulation of a particular circular RNA (circRNA), circCELSR1 (hsa_circ_0063809), and its role in the progression and PTX resistance of ovarian cancer. The high expression of circCELSR1 in PTX-resistant tissues of ovarian cancer and PTX-resistant ovarian cancer cells (SKOV3/PTX and HeyA-8/PTX) was determined by microarray analyses and quantitative real-time PCR. Cell Counting Kit-8 (CCK-8) assays were performed to investigate the effect of circCELSR1 on PTX sensitivity of ovarian cancer cells. Flow cytometer assays were used to detect cell cycle and apoptosis of ovarian cancer cells. The effect of circCELSR1 on ovarian cancer cells was assessed in vitro and in vivo. The microRNA (miRNA) sponge mechanism of circRNAs was demonstrated using dual-luciferase reporter and RNA immunoprecipitation assays. By microarray (5 PTX-resistant ovarian cancer tissues νs 5 PTX-sensitive ovarian cancer tissues) and qRT-PCR (36 normal ovarian tissues and ovarian cancer tissues) we identified circCELSR1 to be dramatically highly expressed in ovarian cancer samples and correlated with PTX resistance. Compared with sensitive cell lines, circCELSR1 was also highly expressed in PTX-resistant ovarian cancer cell lines, and circCELSR1 silencing enhanced PTX-induced cytotoxicity in ovarian cancer cells. Meanwhile, the inhibition of circCELSR1 also caused ovarian cancer cell G0/G1 arrest and an increase in apoptosis. In vivo studies revealed that circCELSR1 was stably inhibited in a xenograft mouse model and inhibited the growth of ovarian cancer. Furthermore, we demonstrated that circCELSR1 acts as a sponge for miR-1252 and verified that forkhead box 2 (FOXR2) is a novel target of miR-1252. In this study, we explored the specific mechanisms of PTX resistance and tumor progress of ovarian cancer due to circCELSR1; presented the circCELSR1-miR-1252-FOXR2 axis and its role in ovarian cancer drug sensitivity and progression; and suggest that the results may provide an experimental basis for clinical application.

MiR-552 promotes ovarian cancer progression by regulating PTEN pathway

BackgroundIncreasing researches have demonstrated the critical functions of MicroRNAs (miRNAs) in the progression of malignant tumors, including ovarian cancer. It was reported that miR-552 was an important oncogene in both breast cancer and colorectal cancer. However, the role of miR-552 in ovarian cancer (OC) remains to be elucidated.MethodsRT-PCR and western blot analysis were used to detect the expression of miR-552 and PTEN. The impact of miR-552 on ovarian cancer proliferation and metastasis was investigated in vitro. The prognostic value of miR-552 was evaluated using the online bioinformatics tool Kaplan-Meier plotter.ResultsIn the present study, we for first found that miR-552 was upregulated in ovarian cancer, especially in metastatic and recurrence ovarian cancer. Forced miR-552 expression promotes the growth and metastasis of ovarian cancer cells. Consistently, miR-552 interference inhibits the proliferation and metastasis of ovarian cancer cells. Mechanically, bioinformatics and luciferase reporter analysis identified Phosphatase and tension homolog (PTEN) as a direct target of miR-552. miR-552 downregulated the PTEN mRNA and protein expression in ovarian cancer cells. Furthermore, the PTEN siRNA abolishes the discrepancy of growth and metastasis capacity between miR-552 mimic ovarian cells and control cells. More importantly, upregulation of miR-552 predicts the poor prognosis of ovarian cancer patients.ConclusionOur findings revealed that miR-552 could promote ovarian cancer cells progression by targeting PTEN signaling and might therefore be useful to predict patient prognosis.

P28GANK overexpression is associated with chemotherapy resistance and poor prognosis in ovarian cancer.

The non-ATPase regulatory subunit 10 of the human 26S proteasome (p28GANK) has been implicated in the tumorigenesis and progression of several types of malignant tumor. The aim of the present study was to detect the expression of p28GANK in ovarian cancer (OC) and investigate its association with the clinicopathological features and prognosis of OC. The expression levels of p28GANK were determined in 114 OC tissue samples and 30 normal ovarian tissue samples using immunohistochemistry. An association was observed between p28GANK overexpression and certain clinicopathological factors, including advanced International Federation of Gynecology and Obstetrics stage (P=0.042), residual tumor size (P=0.005) and response to chemotherapy (P<0.001). Furthermore, patients with high expression of p28GANK demonstrated worse overall survival (OS) and disease-free survival (DFS) rates compared with patients with low expression of p28GANK (both P<0.001). Multivariate Cox regression analysis revealed that overexpression of p28GANK was an independent prognostic factor of OS and DFS in patients with OC (P=0.013 and P=0.001, respectively). In summary, the current results indicate that p28GANK may be a predictive marker and a therapeutic target for OC.

Wnt Signaling in Ovarian Cancer Stemness, EMT, and Therapy Resistance.

Ovarian cancers represent the deadliest among gynecologic malignancies and are characterized by a hierarchical structure with cancer stem cells (CSCs) endowed with self-renewal and the capacity to differentiate. The Wnt/β-catenin signaling pathway, known to regulate stemness in a broad spectrum of stem cell niches including the ovary, is thought to play an important role in ovarian cancer. Importantly, Wnt activity was shown to correlate with grade, epithelial to mesenchymal transition, chemotherapy resistance, and poor prognosis in ovarian cancer. This review will discuss the current knowledge of the role of Wnt signaling in ovarian cancer stemness, epithelial to mesenchymal transition (EMT), and therapy resistance. In addition, the alleged role of exosomes in the paracrine activation of Wnt signaling and pre-metastatic niche formation will be reviewed. Finally, novel potential treatment options based on Wnt inhibition will be highlighted.

Interleukin-17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma.

The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin‐17 (IL‐17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL‐17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL‐17‐producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi‐color flow cytometry (Th17: P < 0.0001 and P = 0.0002, respectively; γδT17: P = 0.0020 and P = 0.0084, respectively). IL‐17 mRNA level was elevated in PBMC of ovarian cancer patients (P = 0.0029), as measured by RT‐PCR. The neutrophil‐to‐lymphocyte ratio, which is a prognostic biomarker of ovarian cancer, correlated with Th17 occupancy ratio in patients (P = 0.0068). We found that programmed cell death 1 ligand 1 expression and its associated factors (IL‐6 and phospho‐signal transducer and activator of transcription 3) were induced by IL‐17 in an ovarian cancer cell line. These results suggest that increased Th17 counts and IL‐17 level, which correlated with high neutrophil‐to‐lymphocyte ratio and programmed cell death 1 ligand 1 expression, are potential biomarkers for poor prognosis in ovarian cancer and likely indications for application of programmed cell death 1 ligand 1 pathway inhibitors.

Decreased DHRS2 expression is associated with HDACi resistance and poor prognosis in ovarian cancer

ABSTRACTHistone deacetylases (HDACs) have been linked to a variety of cancers, and HDAC inhibitors (HDACi) are a promising class of drugs that have demonstrated anti-cancer effects. However, we have little knowledge regarding the selection and application of HDAC inhibitors to the personalized treatment of ovarian cancer (OC). Here, we report a correlation between the high expression of HDACs and poor outcomes in OC patients, which reveals that HDACi are a class of agents that show great promise for the treatment of OC. Furthermore, we found that HDACi increased both the mRNA and protein levels of DHRS2, which has been shown to be closely linked to HDACi sensitivity when it is highly expressed, especially in ovarian cancer cells. Consistently, we found that suppression of DHRS2 reduced the sensitivity of OC cells to HDAC inhibitors via attenuation of the inhibitory effects of HDAC inhibitors on Mcl-1 in vitro. Our study demonstrated that DHRS2 expression was decreased in OC tissues and that high expression of DHRS2 was correlated with better outcomes in OC patients. In addition, DHRS2 expression was closely related to the effects of chemotherapy. Our study reveals the role of DHRS2 in cell apoptosis induced by HDAC inhibitors and explores the clinical attributes of DHRS2 in OC from a new perspective, suggesting that OC patients with high DHRS2 expression may benefit from treatment with HDAC inhibitors.

Matrix Metalloproteinase Expressions Play Important role in Prediction of Ovarian Cancer Outcome

Ovarian cancer has a high death rate and is often not detected until late stages. While some studies found high expressions of MMPs correlated with cancer invasion, metastasis, and poor prognosis, however, several other studies indicated MMPs might inhibit cancer rather than promote cancer in certain situations. Thus, the role of different MMPs in different cancer types needs a systematic re-evaluation. In this study, we used RNA-Seq and corresponding clinical data downloaded from TCGA and analyzed the correlations between MMP expressions and the clinicopathologic characteristics and outcome in ovarian serous cystadenocarcinoma (OSC) patients. Among the MMPs investigated, MMP-3 was significantly increased in high-grade and high-stage tumors compared with low-grade and low-stage ones. Using univariate analysis and multivariate Cox model, high expressions of MMP-19 and -20 were found to associate with poor overall survival independent of clinicopathologic characteristics. Moreover, using in vitro studies, we found ovarian cancer cell lines with higher MMP-19 and -20 protein expressing levels were associated with anti-cancer drugs resistance, while knockdown of MMP-19 or -20 increased ovarian cancer cell sensitivities to several clinical using chemotherapy agents. Finally, knockdown of MMP-19 or -20 also decreased the invasion abilities of several ovarian cancer cell lines. These in vitro studies provided potential mechanisms of high MMP-19 and -20 expressions in the poor prognosis of ovarian cancer.

Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild-type disease during the early disease course.

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA-4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.

Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer

Jumonji domain-containing 6 (JMJD6) is a candidate gene associated with tumorigenesis, and JMJD6 overexpression predicts poor differentiation and unfavorable survival in some cancers. However, there are no studies reporting the expression of JMJD6 in ovarian cancer, and no JMJD6 inhibitors have been developed and applied to targeted cancer therapy research. In the present study, we found that the high expression of JMJD6 in ovarian cancer was correlated with poor prognosis in ovarian cancer. A potential inhibitor (SKLB325) was designed based on the crystal structure of the jmjC domain of JMJD6. This molecule significantly suppressed proliferation and induced apoptosis in a dose-dependent manner in SKOV3 cell lines as detected by CCK-8 cell proliferation assays and flow cytometry. A Matrigel endothelial tube formation assay showed that SKLB325 inhibited capillary tube organization and migration in HUVECs in vitro. We also observed that JMJD6 colocalized with p53 protein in the nucleus, with mRNA and protein expression of p53 as well as its downstream effectors significantly increasing both in vitro and in intraperitoneal tumor tissues treated with SKLB325. In addition, SKLB325 significantly reduced the intraperitoneal tumor weight and markedly prolonged the survival of tumor-bearing mice. Taken together, our findings suggest that JMJD6 may be a marker of poor prognosis in ovarian cancer and that SKLB325 may be a potential candidate drug for the treatment of ovarian cancer.

Downregulated Long Noncoding RNA GAS5 Fails to Function as Decoy of CEBPB, Resulting in Increased GDF15 Expression and Rapid Ovarian Cancer Cell Proliferation.

Introduction: Growth differentiation factor 15 (GDF15), a newly identified member of transforming growth factor (GDF) superfamily, is upregulated in ovarian (OV) cancer. Upregulated GDF15 positively correlates with poor prognosis of OV cancer. Thus, elucidation of the mechanism underlying GDF15 overexpression is important. Method and Results: PROMO and JASPAR prediction software were used to find transcription factors for GDF15 expression. Data from TCGA database were analyzed to find long noncoding RNAs (lncRNAs) that were also abnormally expressed in OV cancer and had associations with GDF15 expression. Transcription factor CEBPB was predicted as an important regulator of GDF15, confirmed by luciferase reporter assay. However, CEBPB expression was not significantly changed in OV cancer. Data from TCGA database showed that lncRNA GAS5 is downregulated in OV cancer and its expression is negatively correlated with GDF15 expression. RPISeq showed high affinity of GAS5 to CEBPB and this was confirmed by RNA-binding protein immunoprecipitation assay. GAS5 overexpression increased its binding to CEBPB and consequently downregulated GDF15. GAS5 overexpression and GDF15 knockdown decreased viability and increased apoptosis of OV cancer cells, but CEBPB overexpression had opposite effects. However, simultaneous GAS5 and CEBPB overexpression or CEBPB overexpression together with GDF15 knockdown had no effect on cell viability and apoptosis. Conclusion: GAS5 functions as decoy of CEBPB, blocking transcription-promoting effect of CEBPB on GDF15.

MiRNA-8073 targets ZnT1 to inhibit malignant progression of ovarian cancer.

The purpose of this study was to investigate the effect of microRNA-8073 on the malignant progression of ovarian cancer (OC) and whether the underlying mechanism is through the regulation of ZnT1 expression. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of microRNA-8073 in 50 tumor tissues and adjacent tissues of OC patients, and the relationship between microRNA-8073 expression and clinical indicators of OC was analyzed. Negative control group (NC) and microRNA-8073 overexpression group (microRNA-8073 mimics) were set in OC cell lines, and the transfection efficiency was further verified by qRT-PCR. In OC cell lines including SKOV3 and OVCAR3, the effects of microRNA-8073 on cell proliferation and apoptosis were analyzed by cell counting kit-8 (CCK-8), cell clone formation assay, and flow cytometry. Finally, the regulatory mechanism of microRNA-8073 on the downstream gene ZnT1 was explored by a recovery experiment. QRT-PCR results revealed that microRNA-8073 expression in cancer tissue specimens of OC patients was significantly lower than that in corresponding normal tissues, and the difference was statistically significant. Compared with patients with high expression of microRNA-8073, NC group had low expression of microRNA-8073 and had a higher pathological stage and lower overall survival rate. In the OC cell lines including SKOV3 and OVCAR3, compared with the NC group, the cell proliferation ability of the microRNA-8073 mimics group was significantly decreased, while the apoptotic ability was significantly increased. Also, ZnT1 had high expression in OC cell lines and tissues and was confirmed negatively correlated with microRNA-8073 level. Meanwhile, the recovery experiment revealed that overexpression of ZnT1 can counteract the effect of microRNA-8073 mimics on OC cell proliferation and apoptosis so as to affect the malignant progression of OC. We demonstrated that microRNA-8073 was significantly associated with the pathological stage and poor prognosis of OC. In addition, microRNA-8073 might inhibit malignant progression of OC by regulating ZnT1 expression.

ABT737 enhances ovarian cancer cells sensitivity to cisplatin through regulation of mitochondrial fission via Sirt3 activation

AimsThe poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. Main methodsApoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. Key findingsCisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. SignificanceThis study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.

High α B-crystallin and p53 co-expression is associated with poor prognosis in ovarian cancer.

Objectives: The present study investigated the correlation between α B-crystallin (CRYAB, HSPB5) and p53 expression in ovarian cancer and further analyzed the relationship between their expression and clinicopathology and the prognostic value of their co-expression in ovarian cancer. Methods: CRYAB and p53 expression was assessed using immunohistochemistry on ovarian cancer tumor tissues from 103 cases and validated in an independent group of 103 ovarian cancer patients. Results: High CRYAB and p53 expression rates in ovarian cancer tissues were 61.17% (63/103) and 57.28% (59/103), respectively, and their expression was positively correlated (r = 0.525, P=0.000). High CRYAB expression was significantly correlated with tumor size (P=0.028), lymph node metastasis (P=0.000), distant metastasis (P=0.005), tumor node metastasis (TNM) stage (P=0.002), and survival (P=0.000), while high p53 expression was significantly correlated with tumor size (P=0.006), pathological grade (P=0.023), lymph node metastasis (P=0.001), and survival (P=0.000). Further studies found that the high CRYAB and p53 co-expression was also significantly correlated with pathological grade (P=0.024), lymph node metastasis (P=0.000), Distant metastasis (P=0.015), TNM stage (P=0.013), and survival (P=0.000). High expression of either CRYAB or p53 and high co-expression of CRYAB and p53 were significantly correlated with poor disease-free survival (DFS) and overall survival (OS), respectively (P<0.05). Patients with high CRYAB and p53 co-expression had the worst prognoses among the groups. In addition, multivariate Cox regression models showed that high expression of either CRYAB or p53 and high co-expression of CRYAB and p53 were independent prognostic factors for DFS and OS (P<0.05). Moreover, the positive correlation and prognostic value of CRYAB and p53 expression were verified in another independent dataset. Conclusions: We demonstrated that patients with high CRYAB and p53 co-expression in ovarian cancer have significantly increased risks of recurrence, metastasis, and death compared with other patients. Therefore, more frequent follow-up of patients with high CRYAB and p53 co-expression is required. Our results also suggest that combination therapy with CRYAB inhibitors and p53 blockers may benefit future treatment of ovarian cancer patients with high co-expression of CRYAB and p53.

GPR30 signaling to regulate epithelial-mesenchymal transition and predict survival in ovarian cancer.

e17041 Background: G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that the high expression of GPR30 is associated with a poor prognosis in breast cancer or endometrial cancer. Although the role of GPR30 in ovarian cancer was unclear, we revealed that GPR30 is associated with poor prognosis in ovarian cancer. On the other hand, Epithelial-to-Mesenchymal Transition (EMT) is involved in cancer metastasis. The purpose of this study is to reveal how GPR30 was associated with poor prognosis and whether associated with EMT in ovarian cancer. Methods: We examined whether GPR30 signaling activates the EGFR-Akt pathway in an ovarian cancer cell line (Caov-3) by a Western blotting analysis. We also examined the effect of GPR30 on EMT were evaluated in Caov-3, which were cultured both in two-dimensional (2D) culture and three-dimensional (3D) culture model. GPR30 agonist, G1, was used to confirm the regulatory effects of GPR30 on the change of phenotypic modulation and EMT markers expression. Results: The phosphorylation of the EGFR and Akt could be significantly enhanced by G1 (p &lt; 0.05) and inhibited by a Src family kinase inhibitor. In 3D culture, the stimulation of GPR30 leads the floating and sphere formation in Caov-3. G1-induced EMT was observed with related regulation of EMT markers expression at both mRNA and protein level. G1 induced the decrease of E-cadherin level and the increase of Snail and Vimentin in RT-PCR and Western blotting. Knockdown of GPR30, using siRNA, blocked G1-induced EMT. Conclusions: GPR30 increases the phosphorylation of Akt via the EGFR in ovarian cancer cells and changes ovarian cancer cells to the EMT state.GPR30 might be an important molecule related to metastasis process in ovarian cancer.

Selective and nonselective GR antagonists in combination with chemotherapy in ovarian cancer PDX models.

e17039 Background: Treatment strategies are needed for platinum-resistant recurrent ovarian cancer. Glucocorticoid receptor (GR) is associated with poor prognosis in ovarian cancer. GR signaling inhibits chemotherapy-induced cell death via transcriptional regulation of anti-apoptotic proteins. Non-selective (mifepristone) and selective GR antagonists (Relacorilant, Corcept Therapeutics) are under clinical development (eg. NCT02046421, NCT03776812). We hypothesized that GR antagonism would improve chemotherapy sensitivity in ovarian cancer patient-derived xenograft (PDX) models. Methods: Five PDX models were selected based on GR expression above median RNA seq levels. Tissues were transplanted into 300 female SCID-Bg mice at the Mayo Clinic. Once tumor diameter reached 0.2 cm, mice were randomized into treatment arms (2-25 mice per arm) and treated intraperitoneal (i.p): control (9% saline, CTL) on day 0 (D0), 1, 7, 8, 14, 15, 21, 22; mifepristone (MIF), 15 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; relacorilant (134), 20 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; carboplatin (CBDCA) at the MTD, 51 mg/kg D1, 8, 15, 22; CBDCA + MIF; CBDCA + 134. Tumor area was measured by ultrasound weekly (D0-D28), and the ratio calculated relative to D0. Tumor growth curves were compared between arms for each PDX via a linear mixed effects regression test of coincident curves. Time to progression was also evaluated and will be presented. Results: In 1/5 models (PH160), CBDCA + MIF significantly suppressed tumor growth compared to CBDCA alone (p &lt; 0.05, Table 1). Addition of 134 to CBDCA did not suppress tumor growth compared to CBDCA alone in any model. In the 2 models with no difference of CBDCA versus CTL (PH160, PH454), addition of a GR antagonist to CBDCA suppressed tumor growth versus CTL. Conclusions: Addition of GR antagonists can improve response to chemotherapy. Work is ongoing to identify the GR transcriptional network, tumor, and host characteristics which predict responses to GR antagonists. [Table: see text]