Development Of Ovarian Tumors Research Articles

Пухлина Бреннера у жінок репродуктивного віку з ожирінням: клініко-морфологічний аналіз випадків із практики

Background. Brenner tumors are rare epithelial ovarian tumors, the incidence of which among all ovarian tumors ranges from 0.6 to 2%. Considering the rarity of the pathology and absence of specific clinical symptoms, the authors present an analysis of own cases from the practice of Brenner tumor. Purpose – familiarization of the medical community with the clinical and morphological features of Brenner tumor in obese women of reproductive age based on an analysis of own practice cases. Materials and Methods. A clinical and morphological analysis of cases from practice of Brenner tumor of different histological variants in obese women of reproductive age is provided. Results. In the first case, in patient V., 42 years old, with obesity, a morphological study of the surgical material was diagnosed a benign variant of the Brenner tumor in the left ovary, which clinically manifested by pain and was not diagnosed by ultrasound. In the second case, in patient G., 36 years old, with obesity, it was morphologically diagnosed a benign variant of Brenner tumor in the right ovary, and borderline variant of Brenner tumor in the left ovary against the background of a benign variant. Brenner tumor in patient G. manifested by pain, infertility in anamnesis, and the presence of cysts on ultrasound examination. The menstrual cycle disorders in women in both cases may be caused by the presence of leiomyomas in the uterus or Brenner tumors or a combination of these tumor pathology. Conclusions. Brenner tumors are rare epithelial ovarian tumors, the only diagnostic method for which is a morphological examination of surgical material. Literature data about the role of obesity in the genesis of the development of these epithelial ovarian tumors, the presence in the described cases from practice of an increased body mass index in women with benign and borderline variants of Brenner tumors actualize the conduct of complex morphological studies in order to search, firstly, the etiopathogenetic features of the development of these ovarian tumors in obese women, and secondly, the morphological differential diagnostic criteria for these epithelial ovarian tumors in women with and without obesity.

I saw the “sea anemone” sign: Puffy face of borderline ovarian tumors

The sea anemone sign is a radiologic sign seen on magnetic resonance imaging (MRI) studies that indicates the morphological development of serous borderline ovarian tumors (SBOTs), as papillary projections originating from the wall of the cystic lesion. The presence of T2 hypointense fibrous stroma in the center of the papilla is a helpful tip in the diagnosis of SBOTs. Those projections might also be assumed to have a frond-like appearance which can be seen as branching papillary projections, especially on T2-weighted imaging.The term “sea anemone” sign is described by Tanaka et al. who deemed it as a “hallmark” feature of surface SBOTs.

Positive effects of rutin on female reproduction.

This article reviews the source and properties of rutin (vitamin P), its general physiological and medicinal effects and their mechanisms, but the main subject of it is the currently available knowledge concerning the character and mechanisms of action of rutin on female reproductive processes. The available data demonstrate the stimulatory action of rutin on female reproductive processes: it can promote ovarian follicles development and ovulation, ovarian cyclicity, and viability of ovarian cells. On the other hand, it can suppress ovarian cancer cell and tumour development by inhibition of cell proliferation and growth and activation of their apoptosis and death. Furthermore, it could be able to prevent other reproductive disorders (ischaemia, polycystic ovarian syndrome, toxic effects of chemotherapy, nanoparticles and toluene). Rutin could exert its effects via changes in the release and reception of gonadotropin, ovarian steroid hormones, prostaglandins, cytokines, VEGF, as well as in intracellular regulators and markers of oxidative and inflammatory processes, proliferation, apoptosis and angiogenesis.

Explainable Artificial Intelligence based Ensemble Machine Learning for Ovarian Cancer Stratification using Electronic Health Records

The purpose of this study is to show how ensemble learning-driven machine learning algorithms outperform individual machine learning algorithms at predicting ovarian cancer on a biomarker dataset. Additionally, this study provides model explanations using explainable Artificial Intelligence methods, The method involved gathering and combining 49 risk factors from 349 patients. We hypothesize that ensemble machine learning systems are superior to individual Machine Learning systems in predicting ovarian cancer. The Machine Learning system consists of five individual Machine Learning and five ensemble Machine Learning systems were trained using K-10 cross validation protocols. These training models were then used to predict the development of benign ovarian tumors and ovarian cancer tumors patients. The AUC and Accuracy metrics for ensemble machine learning increased by 19% and 16%. The MCC and Kappa scores for ensemble Machine Learning also increased over individual machine learning by 29% and 33%, respectively. As a result, we draw the conclusion that ensembled-based algorithms outperform individual machine learning in terms of ovarian carcinoma prediction.

The mechanisms crosstalk and therapeutic opportunities between ferroptosis and ovary diseases.

Ferroptosis, a form of regulated cell death, was first defined in 2012. Ferroptosis mainly involves iron-driven lipid peroxidation damage of cells. This process is regulated by iron homeostasis, redox balance, lipid metabolism, glutathione metabolism, and various disease signaling pathways. Iron is one of the key mineral elements that regulate the physiological function of women and the development of ovarian tumors. Occurrence of Ferroptosis has some hidden dangers and advantages in ovary diseases. Some scholars have shown that ferroptosis of ovarian granulosa cells (GC) promotes the development of ovarian dysfunction and polycystic ovary syndrome (PCOS). Interestingly, drug-resistant ovarian cancer cells are very sensitive to ferroptosis, suggesting that pharmacological positive and negative regulation of ferroptosis has great potential in the treatment of benign ovarian diseases and ovarian cancer. This article aimed to assess how ferroptosis occurs and the factors controlling ferroptosis. Moreover, we summarize how ferroptosis can be used to predict, diagnose and target treatment ovary disease. Meanwhile, we also evaluated the different phenomena of Ferroptosis in ovarian diseases. It aims to provide new directions for the research and prevention of female reproductive diseases.

O-152 Benign epithelial ovarian tumors following use of fertility drugs: a register-based cohort study from Denmark

Abstract Study question Is use of fertility drugs associated with an increased risk of benign epithelial ovarian tumors among women with infertility? Summary answer Among women with infertility, use of fertility drugs is not associated with an increased risk of benign epithelial ovarian tumors. What is known already Benign epithelial ovarian tumors are the most common neoplasms in the ovaries. These benign tumors share some of the same risk factors, which are associated with ovarian cancer. The general understanding of the pathogenesis and etiology of ovarian cancer is sparse; therefore, knowledge on factors influencing development of benign epithelial ovarian tumors—and hence likely ovarian cancer—is warranted. Previous studies on the association between fertility treatment and ovarian cancer are conflicting, whereas no previous study has examined the association between use of fertility drugs and benign epithelial ovarian tumors. Study design, size, duration Retrospective register-based cohort study of nearly 145,000 women included in the Danish Infertility Cohort during 1995–2017 at age 20–45 years. Women were followed from one year after infertility diagnosis until first benign epithelial ovarian tumor or one of the censoring criteria: borderline ovarian tumor, ovarian cancer, oophorectomy, emigration, death or end of follow-up (December 31, 2018). Participants/materials, setting, methods Using the Aalen-Johansen estimator, we determined 10-year cumulative risks of benign epithelial ovarian tumors among approximately 25,000 women who used fertility drugs (defined within one year after infertility diagnosis: clomiphene citrate, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone [GnRH] receptor modulators, and progesterone) compared with women diagnosed with infertility and no drug use. Additionally, we used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Main results and the role of chance Our results showed that the crude 10-year cumulative risk of benign epithelial ovarian tumors were 0.32% (95% CI: 0.29%–0.36%) for women who used any fertility drug compared with 0.49% (95% CI: 0.40%–0.60%) in women with no use of fertility drugs (risk difference: -0.17% [95% CI: -0.28–(-0.07)]). When adjusted for age, calendar period of infertility diagnosis, educational level, parity, obesity, polycystic ovary syndrome, and origin of infertility information, the HR for use of any fertility drug was 0.73 (95% CI 0.55–0.96). In general, the 10-year risk differences as well as the HRs for each drug evaluated separately were similar to the results for use of any drug. Lastly, we tested the robustness of our results by various pre-defined secondary analyses, and this did not change our results. Limitations, reasons for caution We did not include information on number of cycles and treatment regimens as these are only partly available in the registers. Wider implications of the findings Among women with infertility, we observe a lower relative risk of benign epithelial ovarian tumors for women treated with fertility drugs compared with women who did not use fertility drugs. However, this finding translates into a small decrease in absolute risk, which does not appear to have any clinical relevance. Trial registration number Not applicable

Endometriosis-Related Ovarian Cancers: Evidence for a Dichotomy in the Histogenesis of the Two Associated Histotypes.

Evidence indicates that different pathways of malignant degeneration underlie the development of endometriosis-associated ovarian tumors of endometrioid and clear cell histotypes. The aim of this study was to compare data from patients affected by these two histotypes to investigate the hypothesis of a dichotomy in the histogenesis of these tumors. Clinical data and tumor characteristics of 48 patients who were diagnosed with either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer arising from endometriosis (ECC, n = 22) or endometriosis-associated endometrioid ovarian cancer (EAEOC, n = 26) were compared. A previous diagnosis of endometriosis was detected more frequently in the ECC group (32% vs. 4%, p = 0.01). The incidence of bilaterality was significantly higher in the EAOEC group (35% vs. 5%, p = 0.01) as well as a solid/cystic rate at gross pathology (57.7 ± 7.9% vs. 30.9 ± 7.5%, p = 0.02). Patients with ECC had a more advanced disease stage (41% vs. 15%; p = 0.04). A synchronous endometrial carcinoma was detected in 38% of EAEOC patients. A comparison of the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis showed a significantly decreasing trend for ECC compared to EAEOC (p = 0.02). These findings support the hypothesis that the origin, clinical behavior and relationship with endometriosis might be different for these histotypes. ECC, unlike EAEOC, seems to develop within an endometriotic cyst, thus representing a window of possibility for ultrasound-based early diagnosis.

Expression of Salivary Immediate Early Response Gene X-1 as a Predictor of Malignancy in Epithelial Ovarian Tumor

Objective: This diagnostic study aims to determine the expression of salivary IEX-1 as a predictor of malignancy in epithelial ovarian tumors. 
 Methods: Samples were obtained from ovarian cancer patients who were scheduled for elective surgery. Patients' saliva was collected before surgery and used as the study's research material. Research subjects who met the inclusion and exclusion criteria were divided into two groups based on the post-operative histopathological results, benign and malignant epithelial ovarian tumors. The salivary IEX-1 expression was examined using the Real Time qPCR method. We compared and analyzed the salivary IEX-1 expression ​​in benign and malignant epithelial ovarian tumors. 
 Results: The results of this study were obtained from 47 epithelial ovarian tumors subjects, 22 malignant tumors and 27 benign tumors. The mean salivary IEX-1 expression in benign epithelial ovarian tumors was higher (1.976) than the malignant tumors (0.554) (p<0.001). The AUC value of IEX-1 expression was 0.949 (95% CI 0.894-1,000), cut off point of salivary IEX-1 is ≥ 0,9115 with sensitivity 84%, specificity 86,4%, positive predictive value 82.6% and negative predictive value 87.5%. There was a significant correlation between salivary IEX-1 expression and malignant epithelial ovarian tumors with an OR 5.031 (95% CI 2.039-12.4; p<0,001)
 Conclusion: Salivary IEX-1 expression declines in tandem with the development of malignant epithelial ovarian tumors, providing a very sensitive and specific indicator of the presence of these malignant tumors.
 Keywords: Expression of IEX-1, Malignant epithelial ovarian tumor, Salivary IEX-1, Tumor Marker.

СИСТЕМНЫЙ АНАЛИЗ ПРОЦЕССА ДИАГНОСТИКИ ОПУХОЛЕЙ ЯИЧНИКОВ

The article describes an object field of ovarian tumor. An attribute space is divided into four groups: risk factors, clinical attributes, laboratory-obtained data, and instrumentally obtained data. A system-atic analysis of a medical officer diagnosing an ovarian tumor is conducted by three types: benign, borderline, and malignant tumor. A score of an early ovarian tumor development is calculated using the Kulbac rule, and an attribute space is reduced.

Lysophosphatidic acid suppresses apoptosis of high-grade serous ovarian cancer cells by inducing autophagy activity and promotes cell-cycle progression via EGFR-PI3K/Aurora-AThr288-geminin dual signaling pathways.

Lysophosphatidic acid (LPA) and geminin are overexpressed in ovarian cancer, and increasing evidence supports their contribution to ovarian tumor development. Here, we reveal that geminin depletion induces autophagy suppression and enhances reactive oxygen species (ROS) production and apoptosis of high-grade serous ovarian cancer (HGSOC) cells. Bioinformatics analysis and pharmacological inhibition studies confirm that LPA activates geminin expression in the early S phase in HGSOC cells via the LPAR1/3/MMPs/EGFR/PI3K/mTOR pathway. Furthermore, LPA phosphorylates Aurora-A kinase on Thr288 through EGFR transactivation, and this event potentiates additional geminin stabilization. In turn, overexpressed and stabilized geminin regulates DNA replication, cell-cycle progression, and cell proliferation of HGSOC cells. Our data provide potential targets for enhancing the clinical benefit of HGSOC precision medicine.

Loss of Runx1 Induces Granulosa Cell Defects and Development of Ovarian Tumors in the Mouse.

Genetic alterations of the RUNX1 gene are associated with a variety of malignancies, including female-related cancers. The role of RUNX1 as either a tumor suppressor gene or an oncogene is tissue-dependent and varies based on the cancer type. Both the amplification and deletion of the RUNX1 gene have been associated with ovarian cancer in humans. In this study, we investigated the effects of Runx1 loss on ovarian pathogenesis in mice. A conditional loss of Runx1 in the somatic cells of the ovary led to an increased prevalence of ovarian tumors in aged mice. By the age of 15 months, 27% of Runx1 knockout (KO) females developed ovarian tumors that presented characteristics of granulosa cell tumors. While ovaries from young adult mice did not display tumors, they all contained abnormal follicle-like lesions. The granulosa cells composing these follicle-like lesions were quiescent, displayed defects in differentiation and were organized in a rosette-like pattern. The RNA-sequencing analysis further revealed differentially expressed genes in Runx1 KO ovaries, including genes involved in metaplasia, ovarian cancer, epithelial cell development, tight junctions, cell-cell adhesion, and the Wnt/beta-catenin pathway. Together, this study showed that Runx1 is required for normal granulosa cell differentiation and prevention of ovarian tumor development in mice.

Hereditary ovarian cancer

Background. Hereditary genetic mutations are a significant risk factor for malignant transformation of cells and cancer development. Hereditary genetic mutations account for 15 to 25 % of all ovarian carcinomas. Purpose of the study: to summarize data on hereditary ovarian malignancies, namely: genetic defects, features of the clinical course, treatment options, and disease prevention. Material and methods. A systemic search was undertaken using PubMed, Medline, Cochrane Library databases for publications from 1999 to 2021. Results. The review describes the main genetic defects and hereditary cancer syndromes predisposing to the development of hereditary malignant ovarian tumors. The features of the clinical course and response to drug therapy have been presented. This article summarizes clinical guidelines of the professional communities (National Comprehensive Cancer Network (NCCN), American Society Of Clinical Oncology (ASCO), The U.S. Preventive Services Task Force, and European Society For Medical Oncology (ESMO). These guidelines contain early detection strategies and approaches to prevent the development of cancers in mutation carriers. Conclusion. Detection of hereditary cancer syndromes is important for patients and their families. Recognizing hereditary predisposition to cancer is important to allow timely surveillance and preventative interventions for both patients and family members.

P-785 Assisted reproduction techniques and the risk of ovarian tumors

Abstract Study question Are fertility treatments associated with increased risk of subsequent development of ovarian tumors? Summary answer Results from recent studies have been primarily reassuring. However, further investigation is needed to determine whether fertility drug use increases the risk of ovarian tumors. What is known already In the last decades, the number of fertility treatments is rising worldwide due to postponing childbearing to a later age. The increasing exposure to fertility drugs has brought probable long term sequelae into focus, notably correlation with gynaecological malignancies. Two theories on the association between fertility drugs and ovarian cancer have been proposed, the “incessant ovulation” and the “elevated gonadotropin levels” theory. Use of assisted reproduction techniques (ART) is highly associated with many factors that are known to affect ovarian cancer risk such as parity. Study design, size, duration Summary of relevant clinical literature and review of all research studies that address the possible relation of assisted reproductive treatments with ovarian tumors. Participants/materials, setting, methods Published literature in PubMed, Medline and Google Scholar databases from 2011 to 2021 was screened using the following keywords: assisted reproductive techniques, in vitro fertilization, fertility drugs, ovarian cancer, and borderline ovarian tumors. Articles that were written in non- Latin alphabet were excluded for translational reasons. At least two review authors independently evaluated articles for eligibility. Main results and the role of chance Sixteen cohort and three case-control studies were selected. The majority of included studies reported no increase in ovarian cancer risk among subfertile women treated with ART, compared to either general population or subfertile non-treated women. In eight cohort and one case control studies, the type of fertility drug was clearly reported, including clomiphene citrate, gonadotropins, GnRH (gonadotropin releasing hormone) analogues, alone or in mixed protocols, while in the rest, the type of drug was not specified. Some studies showed a trend for a causative role of increasing dosage or number of IVF (in vitro fertilization) cycles, though statistically insignificant. Based on existing data, genetically vulnerable BRCA mutation carriers should not be excluded from use of ART, although extensive information of the potential association of ovarian stimulating drugs with ovarian tumors should be provided. Data on the association of fertility drug use with borderline ovarian tumors were contradictory. All included studies adjusted or matched for one or more possible confounding factors, such as age, parity and oral contraceptive use. Stratification by cause of infertility, showed an increased risk of ovarian cancer in treated women, with female factor infertility, which was more prominent in case of endometriosis. Limitations, reasons for caution High clinical and methodological heterogeneity of the included studies, with adjustment for varying confounding factors, relatively short follow–up periods and small samples sizes were noticed. Wider implications of the findings Ovarian cancer is the deadliest among all gynaecological malignancies. Considering the increasing use of ART worldwide, further clarification of the association between the two is crucial. For this reason larger, prospective studies are needed with sufficient follow-up exceeding 20years so that treated women will reach the ovarian cancer age range. Trial registration number not applicable

Ovarian tumors and genetic predisposition.

Summary of knowledge in the field of ovarian cancer and genetic predisposition. Ovarian tumors are usually diagnosed at advanced stages of the disease and the prognosis for these patients is generally poor. The 5-year overall survival rate, regardless of the histopathological type of tumor, is around 44%. Germline mutations causing hereditary tumor syndromes are predominantly involved in the development of epithelial ovarian tumors. The most common is hereditary breast and ovarian cancer syndrome, which is caused by germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Several other tumor suppressor genes and oncogenes are known to be associated with ovarian tumors and cause other types of tumor syndromes. Inherited tumor syndromes include Lynch syndrome, Peutz-Jegers syndrome, Gorlin syndrome, Li-Fraumeni syndrome and others. The indication for genetic examination of germline mutations is given by a clinical geneticist on the basis of the recommendation of the attending physician. At present, every ovarian tumor, primary peritoneal tumor and tube tumor diagnosed at any age is indicated for genetic testing. Early identification of genes for hereditary cancer syndromes, thanks to rapidly developing molecular genetic methods, is an important step towards personalized treatment of ovarian cancer and preventive measures in families at risk. It is also important to note that a negative molecular genetic test result does not exclude genetic risk.

Abstract 779: A NRF1-driven JRK-mediated β-catenin transcriptional activity contributes to the aggressive growth of ovarian cancer

Abstract Ovarian cancer is the most lethal gynecological cancer, accounting for thousands of cancer-related deaths in the United States every year. Though there has been progress towards understanding ovarian cancer pathogenesis, much is not yet understood about the molecular mechanisms that facilitate chemoresistance and metastasis. Our work has shown that nuclear respiratory factor 1 (NRF1) is highly active in several human cancers, though the role of NRF1 remains largely unexplored in ovarian carcinomas. Therefore, our aim was to examine the role of this transcription factor in ovarian cancer, since understanding its transcriptional landscape may reveal NRF1 or its target genes as possible therapeutic targets for this highly aggressive cancer. The Cancer Genome Atlas (TCGA) was utilized to collect RNA-Seq data from 379 serous cystadenocarcinoma samples, where we found that about 20% of ovarian cancer patients had altered NRF1 expression, showing either high expression or amplification of this transcription factor. Patients with high NRF1 expression were found to have decreased survival compared to patients with low NRF1 expression. NRF1 amplification was also correlated with the overamplification of one of its target genes - Jrk helix-turn-helix protein (JRK) in 26% of the samples. JRK regulates centrosome amplification, and through the production of mitotic spindle abnormalities, centrosome amplification contributes to genomic instability. Further investigation of the relationship between NRF1 and JRK uncovered that protein levels of JRK and β-catenin were significantly higher in NRF1-induced stem-like cells compared to the control group, and JRK is known to bind to β-catenin. Our NRF1 ChIP-Seq analyses showed that promoters of these two genes - JRK and CTNNB1 - were bound to NRF1. The Flow Assorted Cell Sorting (FACS), ChIP-Seq, RNA Seq and confocal microscopic studies suggest that through JRK, NRF1 regulates β-catenin transcriptional activity. Amplified gene expression is the one of the first steps towards oncogene activation, and our findings illustrate that altered NRF1 expression (i.e., overexpression or amplification) coupled with that of JRK influences the prognosis of patients diagnosed with ovarian cancer. The Wnt/β-catenin pathway is also highly active in the aggressive ovarian cancer. In addition to JRK, through the activation of β-catenin, NRF1may also affect the development of ovarian tumors. Taken together, our findings provide a novel insight into the molecular basis of the contribution of NRF1-driven JRK-mediated β-catenin transcriptional activity to the susceptibility of highly aggressive ovarian cancer. A better understanding of how ovarian neoplasm formation depends on NRF1-JRK-β-catenin pathway may open new avenues for therapeutic strategy against ovarian cancer. Citation Format: Ana Ruas, Quentin Felty, Jayanta K. Das, Alok Deoraj, Changwon Yoo, Deodutta Roy. A NRF1-driven JRK-mediated β-catenin transcriptional activity contributes to the aggressive growth of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 779.

MiR-133a targets YES1 to reduce cisplatin resistance in ovarian cancer by regulating cell autophagy

BackgroundAccumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear.ObjectiveTo investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer.MethodsMiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT–qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3′ untranslated region (3′UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT–qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis.ResultsThe expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3’UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance.ConclusionsOur results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

LNC00115 Mediates Cisplatin Resistance by Regulating the miR-7/ERK Signalling Pathway in Ovarian Cancer.

BackgroundOvarian cancer has one of the highest mortality rates among all gynaecological malignancies, and increasing evidence suggests that lncRNAs are widely involved in the development of ovarian tumours. This study aimed to investigate the mechanism of the LNC00115/miR-7/ERK axis in the cisplatin resistance of ovarian cancer cells.MethodsThe expression of miR-7 and LNC00115 in ovarian cancer cell lines and tissues was detected by qRT-PCR. The ovarian cancer cell lines were constructed by overexpressing or knocking down the expression of LNC00115 or miR-7. CCK-8, transwell invasion, Western blot, immunohistochemistry, and luciferase reporter assays were carried out to identify the targets of LNC00115 and explore its roles and mechanisms in ovarian cancer. A nude mouse model was established, and the expression of LNC00115, miR-7 and ERK was detected. The changes in the tumours and body weights of the nude mice were measured.ResultsLNC00115 was upregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. Moreover, LNC00115 promoted the cisplatin resistance, invasion and migration of ovarian cancer cells. LNC00115 was shown to directly target miR-7, and miR-7 was downregulated in ovarian cancer tissues and cisplatin-resistant ovarian cancer cells. miR-7 inhibited the cisplatin resistance, invasion and migration of ovarian cancer cells and directly targeted ERK. ERK was overexpressed in cisplatin-resistant ovarian cancer cells and ovarian cancer tissues. In animal experiments, overexpression of LNC00115 enhanced the cisplatin resistance of ovarian cancer cells, while miR-7 had the opposite effect. Mechanistically, LNC00115 sponged miR-7 to increase the expression of ERK, which in turn enhanced the cisplatin resistance of ovarian cancer.ConclusionOur data clarify the mechanism by which the LNC00115/miR-7/ERK axis promotes cisplatin resistance and provide a new clinical strategy for combating cisplatin resistance in ovarian cancer.

Circulating Biomarkers of Inflammation and Ovarian Cancer Risk in the Nurses' Health Studies.

Chronic inflammation is a well-established mechanism of ovarian carcinogenesis; however, the specific immunogenic processes influencing ovarian tumor development remain unclear. In a case-control study nested within the Nurses' Health Study (NHS) and the NHSII, we examined the association between six inflammatory chemokines and cytokines [B-cell activating factor (BAFF), C-X-C motif chemokine ligand 13 (CXCL13), IL8, soluble(s)IL2-receptor-α(Rα), sIL6Rα] and epithelial ovarian cancer risk. Among 299 epithelial ovarian cancer cases and 334 matched controls, six inflammatory biomarkers were measured in plasma collected 1-24 years before diagnosis or index date using two custom multiplex Luminex panels. ORs and 95% confidence intervals (CI) were estimated for the association between each biomarker and risk using multivariable conditional logistic regression with adjustment for relevant confounders. We additionally assessed heterogeneity in the risk associations by histotype [high-grade serous carcinoma (HGSC) vs. non-HGSC], body mass index, smoking status, menopausal status, and aspirin use. Women with the highest versus lowest quartile (Q) levels of CXCL13 had a 72% increased ovarian cancer risk (OR = 1.72; 95% CI = 1.04-2.83; P trend = 0.007). The positive association with CXCL13 was stronger in magnitude for non-HGSC, overweight or obese women, and postmenopausal women, although only menopausal status demonstrated statistically significant heterogeneity (P interaction = 0.04). The remaining biomarkers were not associated with risk. This first evidence that prediagnostic CXCL13, a B-cell chemoattractant, is associated with an increased risk of epithelial ovarian cancer expands current understanding of the role of inflammation in ovarian carcinogenesis. CXCL13 may represent a novel biomarker for ovarian cancer.

Optimization of 7,12-dimethylbenz(a)anthracene-induced rat epithelial ovarian tumors.

Ovarian carcinoma is the second most common malignant tumor of the female reproductive system and an notable cause of cancer death. The detection and diagnosis of early ovarian carcinomas are still clinical challenges, which calls for imaging studies using early ovarian carcinoma animal models. The present study aimed to optimize the 7,12-dimethylbenz(a)anthracene (DMBA)-induced model of rat ovarian tumors by investigating the delivery methods, induction dose and time of DMBA exposure, and explored the morphological features of tumors using MRI. Three schemes were performed. In scheme one the ovary was covered with absorbable hemostatic gauze loaded with a high concentration of liquid DMBA. For this scheme, 150 Sprague-Dawley rats were divided into three groups depending on the DMBA dose (1.0, 2.0 and 3.0 mg). In scheme two DMBA solution was injected under the ovarian capsule. For this scheme, 159 rats were divided into 0.5, 1.0 and 1.5 mg DMBA groups. In scheme three the ovary was covered with absorbable gauze loaded with a high concentration of solid DMBA. For this scheme 161 rats were divided into 1.0, 2.0 and 3.0 mg DMBA groups. Each group of the three schemes was further subdivided into 60-, 90-, 120-, 150- and 180-day groups. In scheme two, the tumor formation rate was 75.6% (99/131), which was the highest in the 1.5 mg group (86.4%, 38/44) and reached 100% (10/10) on day 120. The induced tumors were serous in 93.9% (93/99) of tumors. Borderline ovarian tumors accounted for 19.2% (19/99) of all tumors, and ovarian cancer accounted for 46.5% (46/99). The mean maximum diameter (MMD) of borderline ovarian tumors was 10.29±3.41 mm, and that of ovarian cancer was 15.19±7.10 mm. MMD of the solid components increased with increasing malignancy. Cystic, cystic-solid and solid tumors were observed. The ovarian subcapsular injection of 1.5 mg DMBA was the best scheme for the rat ovarian tumor model. The present model is ideal for investigating the occurrence, development and imaging of ovarian tumors.

Lipocalin2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway

Lipocalin2 (Lcn2) has been shown to be a vital regulator of tumorigenesis in a variety of different cancers. However, its expression patterns and possible roles in ovarian cancer remain obscure. The aim of this study was to investigate the expression of Lcn2 in ovarian cancer cells and to determine any potential association between Lcn2 and ovarian tumor development and cancer progression. Our results indicated that Lcn2 was upregulated in tumor tissue from ovarian cancer patients as well as in three ovarian cancer cell lines compared to normal tissues and cells. Overexpression of Lcn2 promoted both cell proliferation and migration in ovarian cancer cells. Conversely, knockdown of Lcn2 in cell lines suppressed both migration and proliferation. Moreover, upregulation of Lcn2 contributed to tumor growth in nude mice in vivo. Mechanistically, Lcn2 was found to lead to tumor progression in ovarian cancer cells through activation of the ERK/GSK3β/β-catenin signaling pathway. In summary, Lcn2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway, suggesting that Lcn2 might be a novel therapeutic target for ovarian cancer.