Overall Survival In Epithelial Ovarian Cancer Patients Research Articles

Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

Clinical and bioinformatics analysis of the relationship between LAMA3 DNA methylation expression and platinum resistance and prognosis in epithelial ovarian cancer

Objective: To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism. Methods: (1) The relationship between DNA methylation of LAMA3 and platinum resistance in EOC was evaluated by bioinformatics. (2) A total of 67 EOC patients treated at Guangxi Medical University Cancer Hospital from January 2000 to December 2012 were selected to detect the levels of LAMA3 DNA methylation in EOC tissues using pyrophosphate sequencing technology to explore its diagnostic efficacy for platinum resistance and prognosis in EOC patients. Furthermore, its impact on chemotherapy efficacy and prognosis of platinum resistant EOC patients were also analyzed. Results: (1) Ten proteins highly interacting with LAMA3 were screened from the Gene Interaction Retrieval Platform (STRING) database, including laminin β (LAMB) 3, laminin γ (LAMC) 3, integrin α (ITGA) 6, intestine protein β4 (ITGB4), ITGA3, LAMC1,LAMB2, dystrophin associated glycoprotein 1 (DAG1), LAMB1 and cytochrome P450c17α (COL17A1) protein; kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that LAMA3 and its related interacting proteins participate in the regulation of malignant tumor occurrence and development through signaling pathways such as apoptosis, cell cycle, DNA damage response, epithelial mesenchymal transition (EMT), androgen receptor (AR), estrogen receptor (ER), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), RAS/mitogen activated protein kinase (MAPK), receptor tyrosine kinase (RTK), tuberous sclerosis protein complex (TSC)/mammalian target of rapamycin (mTOR), and their expression levels were related to the sensitivity of chemotherapy drugs such as cisplatin in EOC. (2) Our clinical data analysis found that the LAMA3 DNA methylation level in EOC tissue of the platinum-sensitive group (35 cases) was 71% (25/35), which was higher than 69% (22/32) in the platinum-resistant group (32 cases), with statistically insignificant difference (χ2=0.057, P=0.811). The area under the curve (AUC) of LAMA3 DNA methylation level for assessing platinum resistance in EOC was 0.601, and the AUC for predicting EOC patient prognosis was 0.686. The chemotherapy efficacy of EOC patients with high methylation of LAMA3 DNA was worse than that of patients with low methylation, 50% (12/24) vs 15/15, with statistically significant difference (χ2=10.833, P=0.001). The level of LAMA3 DNA methylation had a significant impact on the progression free survival and overall survival of EOC patients (both P<0.05). Conclusion: The level of LAMA3 DNA methylation has certain diagnostic and predictive value for platinum resistance and prognosis in EOC patients, which may be closely related to the regulatory mechanism, platinum resistance and prognosis of EOC.

CT-based radiomics predicts CD38 expression and indirectly reflects clinical prognosis in epithelial ovarian cancer

BackgroundCluster of differentiation 38 (CD38) has been found to be highly expressed in various solid tumours, and its expression level may be associated with patient prognosis and survival. This study aimed to evaluate the prognostic value of CD38 expression for patients with epithelial ovarian cancer (EOC) and construct two computed tomography (CT)-based radiomics models for predicting CD38 expression. MethodsA total of 333 cases of EOC were enrolled from The Cancer Genome Atlas (TCGA) database for CD38-related bioinformatics and survival analysis. A total of 56 intersection cases from TCGA and The Cancer Imaging Archive (TCIA) databases were selected for radiomics feature extraction and model construction. Logistic regression (LR) and support vector machine (SVM) models were constructed and internally validated using 5-fold cross-validation to assess the performance of the models for CD38 expression levels. ResultsHigh CD38 expression was an independent protective factor (HR = 0.540) for overall survival (OS) in EOC patients. Five radiomics features based on CT images were selected to build models for the prediction of CD38 expression. In the training and internal validation sets, for the receiver operating characteristic (ROC) curve, the LR model reached an area under the curve (AUC) of 0.739 and 0.732, while the SVM model achieved AUC values of 0.741 and 0.700, respectively. For the precision-recall (PR) curve, the LR and SVM models demonstrated an AUC of 0.760 and 0.721. The calibration curves and decision curve analysis (DCA) provided evidence supporting the fitness and net benefit of the models. ConclusionsHigh levels of CD38 expression can improve OS in EOC patients. CT-based radiomics models can be a new predictive tool for CD38 expression, offering possibilities for individualised survival assessment for patients with EOC.

Mutational profiling of mitochondrial DNA reveals an epithelial ovarian cancer-specific evolutionary pattern contributing to high oxidative metabolism.

Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated. Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication. Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients. Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.

Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer

BackgroundThe aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome.MethodsThree hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively.ResultsFor rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15–1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12–2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03–5.88, and OR = 1.64, 95%CI 1.04–2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18–0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02–0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients.ConclusionsOur results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Timing of recurrence and overall survival in epithelial ovarian cancer: A 10-year retrospective review

Background: The timing of recurrence of epithelial ovarian cancer (EOC) after a standard primary treatment is an important indicator of the degree of response of the tumour to treatment. It, however, remains unclear if the timing of recurrence will predict survival outcomes. Aim: This study explored the impact of timing of recurrence after an initial response to standard primary treatment on the overall survival (OS) of patients with EOC. Methods: Data was extracted from the records of patients who underwent standard primary treatment and follow-up after EOC diagnosis between January 2011 and December 2020. The Kaplan-Meier survival estimates and Cox proportional hazards model adjusted for covariates were used for analyses. Results: The risks of recurrence of EOC increased steadily with increasing time from the start of primary treatment from 13.6% in 6-months to 71.0% after 12-months. In the final multivariate analyses, recurrence within 6 months of treatment was a significant independent predictor of poor OS in EOC patients (hazard ratio=7.23, 95%CI: 3.87–13.51, P&lt;0.01). Conclusion: Our study suggests that recurrence within 6-months is an important prognostic predictor of poor OS in EOC. Early tumour recurrence may be a useful surrogate of OS and thus this information should be considered in the design of future tailored randomized controlled trials. Future strategies to improve OS in EOC patients should focus on identifying effective measures to prevent early tumour recurrence.

The Role of the Adipokine Resistin in the Pathogenesis and Progression of Epithelial Ovarian Cancer.

Obesity is a civilization disease associated with an increased risk of developing cardiovascular diseases, diabetes, and some malignancies. The results concerning the relationship between obesity and epithelial ovarian cancer (EOC) are inconclusive. The higher incidence of neoplasms in obese subjects has led to the development of the adipokine hypothesis. Omental adipocyte cells interact with cancer cells, promoting their migration and metastasis via the secretion of adipokines, growth factors, and hormones. One of the adipokines is resistin. It was shown in vitro that resistin stimulates the growth and differentiation of ovarian cancer cells. Moreover, it increases the level of angiogenesis factors, e.g., matrix metalloproteinase 2 (MMP-2) and vascular epithelial growth factor (VEGF). Additionally, resistin induces epithelial–mesenchymal transition (EMT) and stemness in EOC cell lines. A positive correlation has been shown between a higher level of resistin expression and the stage of histological differentiation of EOC or the occurrence of lymph node metastases. In addition, the overexpression of resistin has been found to act as an independent factor determining disease-free survival as well as overall survival in EOC patients. Growing evidence supports the finding that resistin plays an important role in some mechanisms leading to the progression of EOC, though this issue still requires further research.

Expression of lnc-MyD88 and its relationship with the prognosis of patients with epithelial ovarian cancer

Objective: To explore the expression of long non-coding RNA-myeloid differentiation factor 88 (lnc-MyD88) and its relationship with the prognosis of patients with epithelial ovarian cancer (EOC). Methods: A total of 70 EOC patients who underwent initial cytoreductive surgery and platinum-based drugs combined with paclitaxel for 6 to 8 courses were selected at Sichuan Cancer Hospital from January 2016 to January 2019. The fresh cancer tissue specimens were collected. In addition, 28 fresh normal ovarian tissues from patients who underwent surgery for benign gynecological diseases during the same period were collected as control group. Reverse transcription (RT) and real-time quantitative polymerase chain reaction (qPCR) were used to detect the expression of lnc-MyD88 and myeloid differentiation factor 88 (MyD88) mRNA in EOC tissues and normal ovarian tissues. The correlation between the expression of lnc-MyD88 and MyD88 mRNA in EOC was analyzed by Pearson's correlation coefficient. The relationship between lnc-MyD88 expression and clinicopathological characteristics of patients with EOC was analyzed. Kaplan-Meier method was used to calculate the survival rate of patients. The log-rank test was used for univariate survival analysis, and Cox proportional hazard model was used for multivariate survival analysis. Results: (1) RT-qPCR showed that the relative expression level of lnc-MyD88 and MyD88 mRNA in EOC were 0.009 (0.000-0.049) and 0.001 (0.000-0.006), respectively, which were significantly higher than those of normal ovarian tissues (all P<0.01); Pearson's correlation coefficient showed that the expression of lnc-MyD88 and MyD88 mRNA in EOC was positively correlated (r2=0.610, P<0.01). (2) The high expression rate of lnc-MyD88 in EOC patients with lymph node metastasis, distant metastasis and chemotherapy resistance (71%, 64% and 70%, respectively) were significantly higher than the patients in control group (41%, 40% and 35%, respectively; all P<0.05). There were no statistically significant in the high expression rate of lnc-MyD88 in EOC patients with different ages, pathological types, pathological grades, surgical pathological stages, postoperative residual lesion size, and ascites cancer cells (all P>0.05). (3) Univariate analysis showed that surgical pathological staging, lymph node metastasis, distant metastasis, postoperative residual tumor size, and high expression of lnc-MyD88 and MyD88 mRNA significantly affected the progression-free survival (PFS) and overall survival (OS) of EOC patients (all P<0.05), ascites cancer cells were the risk factors that significantly affected PFS in EOC patients (P=0.040); multivariate analysis showed that surgical pathological staging and high expression of lnc-MyD88 and MyD88 mRNA were independent factors affecting PFS and OS in EOC patients (all P<0.05), the size of residual lesions after surgery was an independent factor affecting PFS in EOC patients (P=0.001). Conclusions: The level of lnc-MyD88 expression in ovarian cancer tissues was significantly increased. Lnc-MyD88, as a molecular marker for the poor prognosis of EOC, is related to the expression of MyD88 in EOC, and may be involved in its expression regulation, thereby affecting the survival and prognosis of EOC patients.

Co-Overexpression of GRK5/ACTC1 Correlates With the Clinical Parameters and Poor Prognosis of Epithelial Ovarian Cancer.

Background: The prognosis of epithelial ovarian cancer (EOC) is poor, and the present prognostic predictors of EOC are neither sensitive nor specific. Objective: The aim of this study was to search the prognostic biomarkers of EOC and to investigate the expression of G protein-coupled receptor kinase 5 (GRK5) and actin alpha cardiac muscle 1 (ACTC1) in EOC tissues (both paraffin-embedded and fresh-frozen tissues) and to explore their association with clinicopathological parameters and prognostic value in patients with EOC. Methods: A total of 172 paraffin-embedded cancer tissues of EOC patients diagnosed and operated at the memorial hospital of Sun Yat-sen University between December 2009 and March 2017 and 41 paratumor tissues were collected and the expression of GRK5 and ACTC1 was examined using immunohistochemistry. Furthermore, 16 fresh-frozen EOC tissues and their matched paratumor tissues were collected from the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, between August 2013 and November 2019 and subjected to reverse-transcription quantitative PCR analysis to detect the mRNA expression of GRK5 and ACTC1. Results: The expression of GRK5 and ACTC1 was both higher in cancer tissues than in paratumor tissues. GRK5 expression was positively correlated with ACTC1 expression. In addition, GRK5, ACTC1, and GRK5/ACTC1 expression was associated with the recurrence-free survival and overall survival of EOC patients. Furthermore, multivariate logistic regression analysis indicated that GRK5+/ACTC1+ co-expression, intestinal metastasis, postoperative chemotherapy, platinum resistance, and hyperthermic intraperitoneal chemotherapy were independent prognostic factors of EOC. Conclusion: GRK5 and ACTC1 are both upregulated in EOC compared with those in paratumor tissues. The co-expression of GRK5+/ACTC1+ rather than GRK5 or ACTC1 is an independent prognostic biomarker of EOC.

TRNAGlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression.

Simple SummaryIn the precision medicine era, epithelial ovarian cancer (EOC) is characterized by a high death-to-incidence rate and poor 5-year survival. The identification of novel molecular markers is of utmost importance to guide personalized prognosis. The objective of the present study has been to evaluate, for the first time, the prognostic utility of tRNA-derived fragments (tRFs) in ovarian carcinomas. In this context, we have performed in silico analysis and expression profiling, utilizing a TCGA-OV database, GEO datasets and our two institutionally-independent cohorts. The analysis highlighted the internal tRF derived from tRNAGlyGCC (i-tRF-GlyGCC) as a novel molecular predictor of EOC prognosis. More precisely, elevated i-tRF-GlyGCC levels were correlated with an aggressive phenotype of ovarian tumor and linked to adverse survival outcomes and early progression following debulking surgery and platinum-based chemotherapy. Interestingly, i-tRF-GlyGCC integration in multivariate strategies benefits prognostication and achieves superior patient risk-stratification, supporting precision medicine decisions.Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC.

LncRNA TCF7 Promotes Epithelial Ovarian Cancer Viability, Mobility and Stemness via Regulating ITGB8.

This study aimed to investigate the carcinogenic role of long non-coding RNA T-cell factor 7 (lnc-TCF7) in epithelial ovarian cancer (EOC). Lnc-TCF7 overexpression and shRNA plasmids were transfected into SKOV3 and OVCAR3 cells, followed by measurement of cell proliferation, migration, invasion, apoptosis, stemness, and mRNA profile (via microarray). Besides, lnc-TCF7 expression was measured in tumor and adjacent tissues from 76 EOC patients. Lnc-TCF7 was upregulated in EOC cell lines; its overexpression increased cell proliferation, migration, invasion, but decreased apoptosis and promoted CD44, CD133 expressions, CD44+CD133+ cell proportion, spheres formation efficiency and drug resistance to cisplatin in SKOV3 and OVCAR3 cells. Besides, lnc-TCF7 ShRNA exhibited opposite effects comparing with its overexpression. Microarray analysis revealed 267 mRNAs were modulated by lnc-TCF7 dysregulation, among which ITGB8 was the most dysregulated one, which was validated by subsequent western blot and RT-qPCR. Furthermore, ITGB8 overexpression not only induced proliferation, migration, invasion and stemness, but also attenuated the effect of lnc-TCF7 ShRNA on these functions in SKOV3 and OVCAR3 cells. In addition, lnc-TCF7 was upregulated in tumor tissues and correlated with higher pathological grade, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and worse overall survival in EOC patients. Conclusively, lnc-TCF7 regulates multiple oncogenic pathways, promotes proliferation, migration, invasion, stemness via upregulating ITGB8. It also correlates with advanced tumor features and poor prognosis in EOC, implying its potential as a target for EOC treatment.

Actin Beta-Like 2 as a New Mediator of Proliferation and Migration in Epithelial Ovarian Cancer.

The impact of Actin beta-like 2 (ACTBL2), a novel described actin isoform, on epithelial ovarian cancer (EOC) biology has not been investigated so far. In this study, we analyzed the prognostic and functional significance of ACTBL2 and its regulatory element Nuclear factor of activated T-cells 5 (NFAT5). The expression of ACTBL2 and NFAT5 was examined in tissue microarrays of 156 ovarian cancer patients by immunohistochemistry. Aiming to assess the molecular impact of ACTBL2 on cellular characteristics, functional assays were executed in vitro upon siRNA knockdown of ACTBL2 and NFAT5. ACTBL2 expression was identified as an independent negative prognostic factor for overall survival of EOC patients. EOC cell lines showed a significantly increased mRNA and protein level of ACTBL2 compared to the benign control. In vitro analyses upon siRNA knockdown of ACTBL2 displayed a significantly reduced cellular viability, proliferation and migration. siRNA knockdown of NFAT5 proved a significant molecular interplay by inducing a downregulation of ACTBL2 with a thus resulting concordant alteration in cellular functions, predominantly reflected in a decreased migratory potential of EOC cells. Our results provide significant evidence on the negative prognostic impact of ACTBL2 in EOC, suggesting its crucial importance in ovarian carcinogenesis by modulating cellular motility and proliferation.

Long Noncoding RNA LINC01554 as a Novel Biomarker for Diagnosis and Prognosis Prediction of Epithelial Ovarian Cancer.

Objective This study was aimed at exploring the diagnostic and prognostic value of long noncoding RNA LINC01554 (LINC01554) in epithelial ovarian cancer (EOC) patients. Patients and Methods. The expressions of LINC01554 in 161 EOC patients were analyzed using RT-PCR. The area under the ROC curve (AUC) was used to estimate the effectiveness of LINC01554 for prediction. The chi-square test was performed to explore the association between LINC01554 expressions and clinical characteristics in EOC patients. Kaplan-Meier assays were conducted for the examination of the influence of LINC01554 expression on the overall survival of EOC patients. Multivariate analyses were carried out to further determine prognostic values of LINC01554 expression in EOC patients. Results LINC01554 expressions were strongly downregulated in EOC specimens compared with matched nontumor specimens (p < 0.01). Importantly, LINC01554 provided a high diagnostic performance for the detection of EOC specimens (AUC = 0.7827; p < 0.001). Low expression of LINC01554 was distinctly associated with the FIGO stage (p = 0.034) and distant metastasis (p = 0.007). The assays of survival data (five years) revealed that the 5-year overall survival of the low LINC01554 expression group was distinctly shorter than that of the high LINC01554 expression group (p = 0.0017). Finally, in the multivariate Cox model, LINC01554 expression (RR = 2.863, 95% CI: 1.185-4.421, p = 0.014) was demonstrated to be an independent prognostic factor for overall survival of EOC patients. Conclusions Our findings suggested that LINC01554 is an important EOC-related lncRNA, providing a potential diagnostic, prognostic biomarker and therapeutic target for EOC patients.

Tumor Forkhead Box Q1 Is Elevated, Correlates with Increased Tumor Size, International Federation of Gynecology and Obstetrics Stage but Worse Overall Survival in Epithelial Ovarian Cancer Patients.

Background: Forkhead box Q1 (FOXQ1) regulates epithelial ovarian cancer (EOC) cell proliferation, migration, and invasion; however, its prognostic effect in EOC patients is unclear. This study assessed FOXQ1 expression in EOC patients by immunohistochemical (IHC) staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and to analyze its correlation with EOC patients' clinical features and prognosis. Materials and Methods: FOXQ1 protein level in tumor and adjacent tissues from 173 EOC patients who underwent resection was detected by IHC staining and further scored by a semiquantitative scoring method; meanwhile, FOXQ1 mRNA level in tumor and adjacent tissues from 105 out of 173 EOC patients (whose fresh-frozen tissues were available) was detected by RT-qPCR. Besides, EOC patients' clinical features and survival data were collected. Results: Both FOXQ1 protein (n = 173) and mRNA (n = 105) levels were increased in tumor tissues compared with adjacent tissues (both p < 0.001) in EOC patients. Meanwhile, tumor FOXQ1 protein level was positively correlated with tumor size (p = 0.005) and International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.037), while FOXQ1 tumor mRNA level was only positively correlated with tumor size (p = 0.015) in EOC patients; however, they were not correlated with other clinical features such as histological subtypes, tumor differentiation, peritoneal cytology, and so on (all p > 0.05). Moreover, FOXQ1 protein (p = 0.030) and mRNA (p = 0.011) levels in tumors were both correlated with worse overall survival (OS) in EOC patients. Conclusion: FOXQ1 is elevated in tumor tissues, and its high tumor expression correlates with increased tumor size, elevated FIGO stage, and worse OS in EOC patients.

Construction autophagy-related prognostic risk signature to facilitate survival prediction, individual treatment and biomarker excavation of epithelial ovarian cancer patients

BackgroundExisting clinical methods for prognosis evaluating for Epithelial Ovarian Cancer (EOC) patients had defects of invasive, unsystematic and subjective and little data are available for individualizing treatment, therefore, to identify potential prognostic markers and new therapeutic targets for EOC is urgently required.ResultsExpression of 232 autophagy-related genes (ARGs) in 354 EOC and 56 human ovarian surface epithelial specimens from 7 independent laboratories were analyzed, 31 mRNAs were identified as DEARGs. We did functional and pathway enrichment analysis and constructed protein–protein interaction network for all DEARGs. To screen out candidate DEARGs related to EOC patients’ survival and construct an autophagy-related prognostic risk signature, univariate and multivariate Cox proportional hazards models were established separately. Finally, 5 optimal independent prognostic DEARGs (PEX3, DNAJB9, RB1, HSP90AB1 and CXCR4) were confirmed and the autophagy-related risk model was established by the 5 prognostic DEARGs. The accuracy and robustness of the prognostic risk model for survival prediction were evaluated and verified by analyzing the correlation between EOC patients’ survival status, clinicopathological features and risk scores.ConclusionsThe autophagy-related prognostic risk model can be independently used to predict overall survival in EOC patients, it can also potentially assist in individualizing treatment and biomarker development.

Relationship between ascites volume and clinical outcomes in epithelial ovarian cancer

Ascites is a tumor microenvironment, ascites and massive ascites-induce compression could promote the progression of epithelial ovarian cancer (EOC); however, the impact of ascites volume on clinical outcomes has not been studied extensively. We aimed to investigate the association between ascites volume and clinical outcomes especially platinum resistance in EOC. We retrospectively evaluated a total of 546 EOC patients with respect to the amount of ascites, clinicopathologic factors, and survival. Using the threshold of 1500 ml to classify patients into small- and large-volume ascites groups, we analyzed the correlation between ascites volume and clinicopathological factors, including platinum-free interval (PFI), and prognosis. Patients with large volume ascites were more likely to present with later stage disease, primary platinum-resistant (PPR) cancer, and suboptimal cytoreduction. Prolonged PFI was associated with decreased ascites volume. The large-volume ascites group showed worse progression-free survival (PFS) and overall survival (OS). An increase in ascites volume was associated with an increased risk of disease recurrence (hazard ratio [HR] = 1.115, 95% confidence interval [CI]: 1.035-1.200) and death (HR = 1.213, 95% CI: 1.090-1.350). Ascites was an independent predictor of PFS and OS in EOC patients. A large volume of ascites predicated a shortened PFI, an increased incidence of PPR and suboptimal cytoreduction. Thus, the volume of ascites is a simply available clinical parameter, which could be used to evaluate the prognosis and platinum resistance of EOC patients early, it contributes to formulate individualized treatment plan and improve the outcome of EOC patients.

FOXO1 overexpression is correlated with poor prognosis in epithelial ovarian cancer

To investigate FOXO1 expression in epithelial ovarian cancer (EOC), and to explore its correlation with clinicopathological parameters and prognosis of EOC. Two hundred and sixteen cases of paraffin-embedded EOC and 41 paratumor tissues from 2009 to 2017 that had been pathologically confirmed at the memorial hospital of Sun Yat-sen University were included in this study, and the expression of FOXO1 was performed by immunohistochemistry using a polyclonal antibody specific for FOXO1. FOXO1 protein expression is associated with Recurrence free and overall survival in EOC patients; In addition, FOXO1 expression is associated with age, FIGO stage, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence and differentiation grade; Moreover, in a multivariate model FOXO1 overexpression was an independent predictor of poor survival in EOC. FOXO1 may play a candidate oncogenic role in EOC, and FOXO1 is a useful independent prognostic marker in EOC, and it may provide a candidate target therapy in future.

Prognostic significance of FA score based on plasma fibrinogen and serum albumin in patients with epithelial ovarian cancer.

ObjectiveTo evaluate the significance of fibrinogen and albumin (FA) score based on preoperative peripheral blood plasma fibrinogen and serum albumin in the prognosis of patients with epithelial ovarian cancer (EOC).MethodsPatients’ clinicopathological data of 186 cases of EOC were retrospectively collected, and these patients were divided into three groups according to their FA scores (both plasma fibrinogen and serum albumin abnormal were allocated a score of 2; one of them abnormal were allocated a score of 1; neither of them abnormal were allocated a score of 0; optimal cut-off point is taken as the critical point whether the value is abnormal or not). Correlation between FA score in patients with EOC as well as clinicopathological features and overall survival (OS) was analyzed.Results(1) Receiver operating characteristic curve showed that the optimal cut-off point of plasma fibrinogen in the preoperative peripheral blood of patients with EOC was 3.63 g/L. The optimal cut-off point for serum albumin level was 42.45 g/L. (2) There was no significant difference in age, tumor size, neutrophil count, lymphocyte count, C reactive protein and preoperative tumor marker CA125 between the three groups (FA score=0, FA score=1, FA score=2) (P>0.05). However, there was statistically significant difference in tumor grade, tumor stage and the presence of lymph node metastasis between different FA scoring groups (P<0.05). (3) Univariate and multivariate analyses showed that tumor size, tumor grade, tumor stage, plasma fibrinogen, serum albumin, FA score and tumor marker CA125 were statistically correlated with OS of EOC patients after surgery (P<0.05). The complex index FA score is superior to the single plasma fibrinogen and serum albumin when it comes to predicting prognosis. (4) FA score can better predict the prognosis of postoperative patients with EOC whose tumor size is ≥6 cm, whose EOC is advanced (stages III–IV) (P=0.0138) and whose tumor stage is medium or high grade (P=0.0005).ConclusionFA score is closely related to the clinicopathological characteristics and OS of patients with EOC and is an independent risk factor indicating the prognosis of EOC patients.

Upregulation of lncRNA AB073614 functions as a predictor of epithelial ovarian cancer prognosis and promotes tumor growth in vitro and in vivo.

Upregulation of lncRNA AB073614 is found in some cancer types and involved in tumor development and progression including ovarian cancer. However, the clinical value and functional role of lncRNA AB073614 in epithelial ovarian cancer (EOC) still needed to be investigated. We examined lncRNA AB073614 expression using quantitative real time polymerase chain reaction (qRT-PCR) in 75 paired of EOC tissue samples and adjacent normal tissues. Association of lncRNA AB073614 expression with overall survival (OS) was evaluated using Kaplan-Meier analysis. Univariate and multivariate analysis of factors associated with OS were assessed in EOC patients. After lncRNA AB073614 knockdown using siRNAs, the cell viability and cell colony forming assays were performed. Western blot analysis was used to assess relative protein expression. In present study, we demonstrated that lncRNA AB073614 was significantly upregulated in ovarian cancer tissues compared to adjacent normal tissues in patients. Higher lncRNA AB073614 expression significantly associated with tumor size, lymph node invasion, FIGO stage, and shorter OS rate of EOC patients. Furthermore, multivariate Cox regression analysis results showed that higher lncRNA AB0736141 was identified as an independent risk factor of OS in EOC patients. Moreover, we demonstrated that lncRNA AB0736141 knockdown suppressed EOC cell proliferation ability and cell colony formation in vitro. In vivo, we showed that AB0736141 knockdown suppressed tumor growth. We also revealed that lncRNA AB0736141 knockdown inhibited the PTEN/PI3K/AKT signaling pathway in EOC. Thus, these results indicated that LncRNA AB073614 may serve as a prognostic biomarker and potential target of treatment for EOC.