Journal of Ovarian Research最新文献

Background: Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHDIL) is an oncogene with abnormal expression in ovarian cancer (OC), but its regulatory role in the malignant biological properties of OC cells and its mechanisms have not been reported.

Methods: In this study, CHD1L and polo-like Kinase 1 (PLK1) expression in OC tissues and OC cell lines was analyzed. After CHD1L silencing, CAOV-3 cell proliferation and apoptosis were detected by CCK8 assay, EDU and TUNEL staining. Flow cytometry was used to detect cell cycle. CCK8 assay and TUNEL were used to detect the role of CHD1L in the sensitivity of OC cells to cisplatin. In addition, the abilities of CAOV-3 cell migration and invasion were evaluated using wound healing assay and transwell assay. Next, the binding between CHD1L and PLK1 was investigated using co-immunoprecipitation assay. Then, PLK1 was overexpressed to perform the rescue experiments to analyze the regulation mechanism of CHD1L on OC development and cisplatin sensitivity. Moreover, the transplantation tumor model of CAOV-3 cells in nude mice was established to explore the antineoplastic effect of CHD1L downregulation in vivo.

Results: CHD1L was highly expressed in OC tissues and OC cells. Interference with CHD1L significantly inhibited proliferation, promoted apoptosis, induced cycle arrest, suppressed migration and invasion as well as enhanced the sensitivity of CAOV-3 cells to cisplatin. Additionally, CHD1L could interact with PLK1. PLK1 upregulation restored the impacts of CHD1L knockdown on the proliferation, apoptosis, cycle arrest, migration, invasion and the sensitivity of OC cells to cisplatin. It could be also found that CHD1L knocked down limited the tumor volume, downregulated PLK1, Ki67 and cleaved caspse3 expression.

Conclusion: Taken together, interference with CHD1L inhibited the malignant progression and enhanced cisplatin sensitivity of OC cells by binding PLK1.

Background: As current literature does not provide sufficient data to support clear guidelines in patients with a rare adult-type granulosa cell tumor, we aim to investigate: (1) whether additional staging surgery following primary surgical treatment is necessary; (2) how long standard follow-up should be and (3) risk factors for disease recurrence.

Methods: A national multicenter prospective study was initiated in April 2018. Patients with suspected or confirmed adult-type granulosa cell tumor were eligible. Data on staging, follow-up and risk factors were both retrospectively and prospectively collected from medical records, and patients were followed until April 2024 or until death. Descriptive statistical analysis and survival analysis were performed using Cox regression methods and Kaplan-Meier analyses.

Results: In total, 208 patients with histopathologically confirmed adult-type granulosa cell tumor were included, with a median follow-up of 5.5 years (IQR: 2.2-12.3 years). Vaginal bleeding and abdominal pain were the most common symptoms at diagnosis. Median time until first recurrence was 4.2 years (range 2 months- 32 years). Additional staging surgery did not reduce the risk of recurrence. During follow-up, most patients had no symptoms at the time of detection of recurrence. No difference in overall survival was found between patients who were diagnosed with a recurrence during follow-up, and those who were no longer in follow-up and presented with symptoms.

Conclusions: Staging surgery does not improve recurrence free survival in patients with adult-type granulosa cell tumor. Our results suggest that adult-type granulosa cell tumor patients can be discharged from follow-up of adult-type granulosa cell tumor after five years.

Background: Tumor-associated macrophages (TAM) are critical elements of intercellular communication in tumor microenvironment (TME), and exosomes are key mediators between tumor cells and the TME. According to previous reports, miRNAs exert a pivotal role in ovarian cancer (OC) development. The purpose of this work was to explore the function of TAM-derived exosomal miR-589-3p in OC development and elucidate the underlying molecular mechanisms.

Methods: First, peripheral blood mononuclear cells (PBMC) were treated with IL-4 and IL-13 to polarize them into M2-type macrophages. Exosomes were separated from M2-type macrophages, and the physical properties of exosomes were evaluated using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Next, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was applied to examine the expression of relevant genes. Subsequently, Targetscan and miRDB were utilized to predict miR-589-3p target genes, and then the interaction between miR-589-3p and BCL2L13 was verified by dual luciferase assay and RNA Binding Protein Immunoprecipitation (RIP) assay. Finally, Cell Counting Kit-8 (CCK-8) and flow cytometry experiments were employed to explore the changes in the proliferative and apoptotic abilities of OC cells.

Results: In this research, we demonstrated that TAM-derived exosomes facilitated OC cell proliferation and suppressed OC cell apoptosis. Then, qRT-PCR results indicated that miR-589-3p were markedly elevated after co-culture of TAM-derived exosomes with OC cells. In addition, we discovered that miR-589-3p was bound to BCL-2-like protein 13 (BCL2L13), which was confirmed through luciferase assay and RIP assay. Furthermore, functional analysis displayed that TAM-derived exosomes treated with miR-589-3p inhibitor attenuated the promotion of OC cell progression by exosomes.

Conclusion: TAM-derived exosomal miR-589-3p enhanced OC progression through BCL2L13, which offers a novel for OC therapy.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by elevated androgen levels, ovarian cysts, and impaired ovulation in females. This condition is closely linked with various reproductive health issues and has significant impacts on endocrine and metabolic pathways. Patients with PCOS commonly exhibit hyperandrogenaemia and insulin resistance, leading to complications such as acne, hirsutism, weight fluctuations, and metabolic disturbances, as well as an increased risk for type 2 diabetes, cardiovascular disease, and endometrial cancer. Although extensive research has identified several mechanistic aspects of PCOS, a thorough understanding of its pathophysiology remains incomplete. This review aims to provide a detailed analysis of the physiological and pathological aspects of PCOS, covering endocrine, metabolic, and inflammatory dimensions, to better elucidate its etiological framework.

Background: The process of epithelial-mesenchymal transition (EMT) may promote fibrosis in ovarian tissue related to polycystic ovary syndrome (PCOS), thus affecting ovarian function and hormonal balance.

Objective: This study aimed to explore key genes associated with EMT in PCOS and their potential molecular regulatory mechanisms, exclusively from the perspective of transcriptomics and single-cell RNA sequencing (scRNA-seq), combined with Mendelian Randomization (MR) analysis.

Methods: The dataset for PCOS and EMT-related genes (EMT-RGs) were sourced from public databases. The key genes in this study were identified via differential expression analysis, MR, and evaluation of expression levels. Enrichment analysis and a series of functional analyses were conducted on these genes to further elucidate their potential mechanisms. Subsequently, using scRNA-seq data and validation of the expression of key genes, key cell group in PCOS were identified, followed by pseudo-time and cell communication analyses to provide deeper insights.

Results: Three key genes, NUCB2 [odds ratio (OR) = 0.8634, 95% confidence interval (CI): 0.8145-0.9152, P < 0.0001], PGF (OR = 0.8393, 95% CI: 0.7185-0.9805, P < 0.05), and CRIM1 (OR = 0.7539, 95% CI: 0.6556-0.670, P < 0.0001), were identified as having a unidirectional causal association with PCOS and were associated with a reduced risk of PCOS. In public datasets, NUCB2 exhibited significantly increased expression in PCOS samples, while PGF and CRIM1 showed the opposite trends. These three genes were enriched in pathways related to cellular functions, metabolic processes, and the operation of the nervous system, and they were co-expressed in smooth muscle. Additionally, five cell clusters were annotated, among which fibroblasts were identified as key cells due to their highest expression of all three key genes. Further analysis revealed a bifurcation event occurring during the mid-development stage of fibroblasts, with PCOS samples displaying a higher abundance of fibroblasts. In PCOS samples, fibroblasts exhibited more extensive communication with secretory epithelial cells, indicating a more complex intercellular interaction within this condition.

Conclusion: This study identified three EMT-RGs: NUCB2, PGF, and CRIM1, which were associated with a reduced risk of PCOS, with fibroblast identified as a key cell group in the disease's pathology. This provides new insights for PCOS research.

Background: The existing drugs for ovarian cancer (OC) are unsatisfactory and thus new drug targets are urgently required. We conducted proteome-wide Mendelian randomization (MR) and colocalization analysis to pinpoint potential targets for OC.

Methods: Data on protein quantitative trait loci (pQTL) for 734 plasma proteins were obtained from large genome-proteome-wide association studies. Genetic associations with OC were derived from the Ovarian Cancer Association Consortium, which included 25,509 cases and 40,941 controls. MR analysis was performed to evaluate the association between the proteins and the OC risk. Colocalization analysis was conducted to check whether the identified proteins and OC shared causal variants. In addition, the phenome-wide MR analysis was performed to clarify protein associations across the phenotype, and drug target databases were examined for target validation.

Results: Genetically predicted circulating levels of 44 proteins were associated with OC risk at Benjamini-Hochberg correction. Genetically predicted 17 proteins had evidence of the increased risk of OC (CLEC11A, MFAP2, TYMP, PDIA3, IL1R1, SPINK1, PLAU, DKK2, IL6ST, DLK1, LRRC15, CDON, ANGPTL1, SEMA4D, AKR1A1, TNFAIP6, and FCGR2B); 27 proteins decreased the risk of OC(SIGLEC9, RARRES1, SPINT3, TMEM132A, HAVCR2, CNTN2, TGFBI, GSTA1, HGFAC, TREML2, GRAMD1C, ASAH2, CPNE1, CCL25, MAPKAPK2, POFUT1, PREP, NTNG1, CA10, CACNA2D3, CA8, MAN1C1, MRC2, IL10RB, RBP4, GP5 and CALCOCO2). Bayesian colocalization demonstrated that GRAMD1C, RBP4, PLAU, PDIA3, MFAP2, POFUT1, MAN1C1 and DKK2 shared the same variant with OC. The phe-MR analyses assessed the side effects of these 44 identified proteins, and the drug target database offered information on both approved and investigational indications.

Conclusion: This study provides proof of a causal relationship between genetically predicted 44 proteins associated with OC risk, which could serve as promising drug targets for OC.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The quality of oocytes in PCOS patients remains poor, leading to poor pregnancy outcomes. The molecular mechanisms underlying the poor quality of oocytes in PCOS are not fully understood. This study aimed to explore the potential functional microRNAs (miRNAs) in follicular fluid (FF)-derived extracellular vesicles (FF-EVs) and their role in oocyte developmental competence in PCOS. We analyzed DEmiRNAs in FF-EVs and DEGs in oocytes from PCOS patients and controls using GEO database. We identified 14 potential functional DEmiRNAs in FF-EVs and predicted the target genes of 14 DEmiRNAs using TargetScan. We performed conjoint analyses between the target genes of these miRNAs and DEGs in oocytes, identifying 12 DEmiRNAs whose target genes overlap with oocyte DEGs. Thus, 12 functional DEmiRNAs were the hub miRNAs. These miRNAs were predicted to target genes involved in oocyte development and signaling pathways such as PI3K/Akt, Ras, and MAPK pathways. KEGG enrichment analysis suggested that these miRNAs might impair oocyte developmental competence in PCOS by dysregulating PI3K/Akt signaling pathway. qRT-PCR validated the increase of miR-93-3p and miR-152-3p, and the decrease of miR-625-5p and miR-17-5p in FF-EVs of PCOS patients. This study highlighted the significance of FF-EVs in the pathology of PCOS and revealed the potential role of the increase of miR-93-3p and miR-152-3p, and the decrease of miR-625-5p and miR-17-5p in impairing oocyte developmental competence in PCOS. Further research is needed to elucidate the specific mechanisms by which these miRNAs affect oocyte development and to explore the potential therapeutic implications.

Background: To investigate the effect of preoperative immunonutritional status on prognosis in epithelial ovarian cancer patients.

Methods: A multicenter real-world study included 922 patients with histologically confirmed epithelial ovarian cancer who received comprehensive staged surgery or debulking surgery at seven tertiary hospitals in China between 2012 and 2023. Prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) were used to assess the immunonutritional status for their superior predictive power to indicate the nutritional status and the inflammatory immunity. Cox regression analyses were employed to identify variables associated with progression-free survival (PFS) and overall survival (OS).

Results: In the early-stage cohort of 224 epithelial ovarian cancer patients, the optimal cut-off value for PNI was 47.47 for both PFS and OS, while the optimal cut-off value for SII values were 551.37 for PFS and 771.78 for OS. In the late-stage group of 698 patients, the optimal PNI thresholds were 47.76 for PFS and 46.00 for OS, with SII values of 720.96 for PFS and 1686.11 for OS. In multivariate analysis of early-stage patients, high PNI was an independent protective factor for PFS (hazard ratio (HR), 0.39 (95% confidence interval (CI) 0.20-0.76), P = 0.006) and OS (HR, 0.44 (95% CI 0.20-0.97), P = 0.042), respectively. High SII was significantly associated with PFS (HR, 2.43 (95% CI 1.23-4.81), P = 0.011) and marginally unfavorable for OS (HR, 2.05 (95% CI 0.96-4.39), P = 0.064). In advanced population, PNI (HR, 0.77 (95% CI 0.60-0.99), P = 0.043) and SII (HR, 1.34 (95% CI 1.01-1.78), P = 0.041) were independent prognostic factors for OS but had no impact on PFS (P = 0.185, P = 0.188, respectively).

Conclusion: Poor preoperative immunonutritional status has a deleterious effect on the prognosis of patients with ovarian cancer. Intervention in patients suffering from suboptimal preoperative immunonutritional status may facilitate improved survival outcomes.

Introduction: Early diagnosis of ovarian cancer, using cost-effective and non-invasive methods remains an unmet medical need, largely due to unspecific symptoms of the disease.

Objective: Our goal was to identify differentially methylated CpG loci between cervical swabs obtained from patients diagnosed with benign ovarian disease and with malignant pelvic mass.

Methodology: Using Infinium EPICv2 array, we interrogated methylation profiles of 77 cervical swabs. The study cohort was then divided into a training and testing set to develop a diagnostic signature. We applied several strategies to pinpoint CpG sites able to differentiate cervical swabs obtained from ovarian cancer patients and patients with benign ovarian disease.

Results and conclusions: None of the statistical methods applied identified CpG loci capable of diagnosing ovarian cancer with sufficient specificity and sensitivity. We conclude that methylation differences observed do not adequately distinguish between benign and malignant ovarian disease. The variations attributable to clinical conditions are likely obscured by the differences in cell composition, which is the primary source of sample heterogeneity. Therefore, we suggest that diagnostic tools should not rely on local methylation profile of the cervix but rather focus on detecting cancer-specific sequences transferred from the tumor site and present in cervical swabs. Ovarian cancer is difficult to detect early, and we aimed to explore whether DNA methylation in cervical swabs could serve as a diagnostic tool. However, our study found that methylation patterns in these samples do not reliably distinguish between benign and malignant conditions, likely due to variations in cell composition. We recommend future research focus on detecting tumor-specific DNA sequences in cervical swabs instead.