microRNAs In Ovarian Cancer Research Articles

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

IntroductionOvarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. Materials and methodsADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. ResultsADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. ConclusionADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

Overexpression of miR-493-3p suppresses ovarian cancer cell proliferation, migration and invasion through downregulating DPY30

Accumulating evidence has verified that the aberrant expression level of miR-493−3p is often associated with the occurrence of numerous cancers. Nevertheless, the expression level and effect of this microRNA in ovarian cancer (OC) remain largely unclear. Therefore, the molecular function of miR-493−3p in OC progression was systematically investigated in this study.The expression of miR-493−3p and DPY30 was assessed by qRT-PCR. The protein expression level of DPY30 in cell lines was further assessed by western blot. Cell viability was respectively examined in vitro functional experiments including CCK-8 assay, EdU assay, wound healing assay, colony formation and apoptosis assays as well as the scratch test and transwell assay. Bioinformatics analysis and luciferase reporter assays were performed to predict and clarity of the correlation between miR-493−3p and DPY30.The expression of miR-493−3p was significantly reduced in OC tissues and cells. Functional experimental results showed that miR-493−3p suppressed cellular proliferation, migration, invasion, but promoted apoptosis in OC cells. Mechanistically, we also confirmed that DPY30 could be directly targeted by miR-493−3p based on bioinformatics and dual-luciferase reporter analysis. Rescue experiments results indicated that the inhibitory effect of miR-493−3p on cellular proliferation, migration and invasion and the promotive effect of miR-493−3p on apoptosis was abolished by DPY30 overexpression.Our findings demonstrated the antitumor effect of miR-493−3p through targeting DPY30 in ovarian cancer, indicating that miR-493−3p might represent a promising target for ovarian cancer diagnosis and treatment.

The lncRNA SNHG15/miR-18a-5p axis promotes cell proliferation in ovarian cancer through activating Akt/mTOR signaling pathway.

Here, we report the expression pattern, function and regulatory mechanism of SNHG15 together with miR-18a-5p micro RNA in ovarian cancer (OC) for the first time. We recruited 20 patients and took normal ovarian tissues and ovarian tumor tissues from them. We used cell culture, transfection, in vivo tumor xenograft assay, and multiple types of detection assays to investigate the expression and regulation of long noncoding RNA (lncRNA) SNHG15/miR-18a-5p in ovarian tissues and cells. Results: We found that the messenger RNA expression level of SNHG15 was significantly higher and miR-18 was decreased in ovarian cancer tissues and in OC cells. Functional experiments showed that SNHG15 overexpression potentiated the migration and invasion of OC cells, while SNHG15 inhibition reduced the tumor proliferation, which was restored via overexpression of miR-18a. SNHG15 was found to directly target and suppress the expression of miR-18a. Our results illustrate the possible molecular mechanism of lncRNA SNHG15/miR-18a-5p functions in cell proliferation in OC. SNHG15/miR-18a promoted the progression of OC cells via the protein kinase B/mammalian target of rapamycin signaling pathway.

The diagnostic, prognostic and therapeutic potential of circulating microRNAs in ovarian cancer.

Ovarian cancer (OC) is often diagnosed at an advanced stage because of the late onset of symptoms, and this together with the lack of effective treatments, has meant it is associated with a very high mortality. The aberrant expression of MicroRNA (miRNA) contributes to the initiation and development of human tumors including OC. Several miRNAs are secreted by tumor cells and can be identified in body fluids. Serum miRNAs levels are associated with several clinical conditions, and may be used to predict prognosis and response to treatments in some cancers including OC. This review summarizes the current progresses regarding the potential applications of circulating miRNA as innovative biomarkers in OC.

Evaluation of miR-22 and miR-21 as diagnostic biomarkers in patients with epithelial ovarian cancer.

Among the 11 most common cancers, ovarian cancer is the fifth leading cause of death after lung, breast, colorectal and pancreatic cancer. Although diagnosis of ovarian cancer in early stages is followed by various successful treatments, no accurate and reliable method is available at present. Currently microRNAs are being explored as signature biomarkers for early detection of various types of cancer. However little information is available on expression and correlation of microRNA in ovarian cancer. In this study, we have chosen two microRNA on the basis of their altered frequency in epithelial ovarian cancer cases. The main objective of this study is to evaluate the expression of microRNA-22 and microRNA-21 along with various clinicopathological parameters. Expression level of microRNA-22 and microRNA-21 in different stages and subtypes of epithelial ovarian carcinoma has been analyzed to find out its role as a potential diagnostic biomarker. Present study has been conducted in the serum of 80 epithelial ovarian cancer patients and 80 age matched healthy women. Quantitative real time PCR was used to compare the expression of miR-22 and miR-21 between the cases and control groups. Statistical analysis showed 7.85-fold increase in miR-21 expression and 2.1-fold reduction in miR-22 expression of ovarian cancer patients. Increased serum level of miR-21 in ovarian cancer patients and decreased level of miR-22 has been correlated with advanced international federation of gynecology and obstetrics (FIGO) stage and histological sub types of epithelial ovarian cancer. Serous ovarian carcinoma was the most common cancer in the present study. Calculated fold change value for miR-21 was 3.98 and - 2.86 for miR-22 in serous ovarian cancer. Fold change value in the miR-21 expression in advanced stage was 6.29 and 4.25 in early stage. Whereas lower calculated fold change was observed for miR-22 in advanced stage than in early stage (- 2.16). Present study revealed up-regulated expression of miR-21 and down regulated expression of miR-22 in the serum of epithelial ovarian cancer patients. Both of these could be validated as good diagnostic biomarkers for early detection of ovarian cancer.

Role of microRNAs as Clinical Cancer Biomarkers for Ovarian Cancer: A Short Overview.

Ovarian cancer has the highest mortality rate among gynecological cancers. Early clinical signs are missing and there is an urgent need to establish early diagnosis biomarkers. MicroRNAs are promising biomarkers in this respect. In this paper, we review the most recent advances regarding the alterations of microRNAs in ovarian cancer. We have briefly described the contribution of miRNAs in the mechanisms of ovarian cancer invasion, metastasis, and chemotherapy sensitivity. We have also summarized the alterations underwent by microRNAs in solid ovarian tumors, in animal models for ovarian cancer, and in various ovarian cancer cell lines as compared to previous reviews that were only focused the circulating microRNAs as biomarkers. In this context, we consider that the biomarker screening should not be limited to circulating microRNAs per se, but rather to the simultaneous detection of the same microRNA alteration in solid tumors, in order to understand the differences between the detection of nucleic acids in early vs. late stages of cancer. Moreover, in vitro and in vivo models should also validate these microRNAs, which could be very helpful as preclinical testing platforms for pharmacological and/or molecular genetic approaches targeting microRNAs. The enormous quantity of data produced by preclinical and clinical studies regarding the role of microRNAs that act synergistically in tumorigenesis mechanisms that are associated with ovarian cancer subtypes, should be gathered, integrated, and compared by adequate methods, including molecular clustering. In this respect, molecular clustering analysis should contribute to the discovery of best biomarkers-based microRNAs assays that will enable rapid, efficient, and cost-effective detection of ovarian cancer in early stages. In conclusion, identifying the appropriate microRNAs as clinical biomarkers in ovarian cancer might improve the life quality of patients.

MicroRNAs in ovarian cancer and recent advances in the development of microRNA-based biosensors.

Ovarian cancer is the most aggressive of all gynaecological malignancies and is the leading cause of cancer-associated mortality worldwide. Over the recent years, there has been a sharp increase in this mortality rate, mostly due to late diagnosis, which can be attributed to the lack of an early and specific biomarker. Under this scenario, recent interest has shifted towards ovarian cancer associated miRNAs which play strong regulatory roles in various cellular processes. miRNAs have emerged as promising non/minimally invasive cancer biomarkers for improved diagnostic, prognostic and streamlined therapeutic applications. A large number of miRNA assays have been reported that are based on nucleic acid detection-based techniques such as RT-qPCR, microarrays and RNA sequencing methods. Despite demonstrating commendable analytical performances, these laboratory-based techniques are expensive and hence not ideally suited for routine use in resource-limited settings. In recent years, considerable attention has been dedicated to the development of relatively simple, rapid and inexpensive miRNA biosensor strategies. Among these, electrochemical sensors have shown a great promise towards point-of-care diagnostics, due to their inherent advantages such as simplicity, sensitivity, amenability to high levels of multiplexing as well as low cost. In this paper, we provide an overview of the potential role of miRNAs in ovarian cancer, as well as recent advances in the development of nanotechnology-based, optical, and electrochemical biosensing-strategies for miRNA detection.

Identifying and targeting angiogenesis-related microRNAs in ovarian cancer.

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.

MicroRNA in Ovarian Cancer: Biology, Pathogenesis, and Therapeutic Opportunities.

Ovarian cancer comprises one of the three major malignant tumor types in the female reproductive system. The mortality rate of this cancer is the highest among all gynecological tumors, with ovarian cancer metastasis constituting an important cause of death. Therefore, markers for disease prediction and prognosis are highly desirable for early diagnosis as well as for helping optimize and personalize treatment. Recently, microRNAs (miRNAs), which consist of short-sequence RNAs that do not encode a protein, have emerged as new biomarkers in the clinical diagnosis and treatment of ovarian cancer. By pairing with bases specific to the target messenger RNA (mRNA), miRNAs cause degradation of the target mRNA or inhibit its translation, thereby regulating various cellular processes including cell proliferation and adhesion. Increasing numbers of studies have shown that miRNA expression abnormality plays an important role in the development of ovarian cancer. In this review, we discuss the mechanisms of miRNA action, current research regarding their role in the suppression or promotion of ovarian cancer, and their use as markers for diagnosis of prognosis or as therapeutic targets for this disease. Finally, we present future perspectives regarding the clinical management of ovarian cancer and the role for miRNAs therein.

Micro RNAs in Ovarian Cancer

Over kanseri kadinlarda olumler arasinda 5. en sik olum nedeni olan kanserdir. Over kanseri tani ve tedavisi icin gunumuzde standart olarak jinekolojik muayene, ultarason ile degerlendirme ve CA-125 gibi serum olcumleri yer almaktadir. Ancak hem hastaligin tanisi ve tedavisi ile yol gosterebilecek yeni biyobelirteclere yogun bir ihtiyac bulunmaktadir. Kisa, protein kodlamayan RNA’lar olan mikroRNA’lar (miRNA), ozellikle kanserde biyobelirtec olmak icin oldukca kullanisli stabil endojen RNA’lardir. Bu derleme kapsaminda over kanserinde miRNA’larin bugune dek yapilan calismalarda ki rolunun irdelenmesi amaclanmistir.

The Diagnostic and Prognostic Role of Serum MicroRNAs in Ovarian Cancer

AimSummarize the research progress of serum miRNAs in clinical application for early diagnosis and prognosis of ovarian cancer. MethodsReview of the recently published literature these was conducted. We selected reviews and clinical researches from different scientific societies.ResultsThe abnormal expression of serum miRNAs has a certain clinical value in theearly diagnosis of ovarian cancer. Many miRNAs, which are involved in regulating ovarian cancer cell growth, migration, and drug resistance, are also closely related to the patients’ survival rate and affect the prognostic condition of the patients. So the serum miRNAs may be useful diagnostic and prognostic biomarkers.Conclusions Studies have shown that serum miRNAs has the tumor specificity and high stability, enabling it has the potential for early diagnosis, prognosis and sensitivity to chemotherapy. However, the researches on serum miRNAs is still at the primary stage, further researches is needed for application of serum miRNAs in early diagnosis and prognosis of ovarian cancer.

PO-321 MicroRNA-145 and COX2 levels are regulated by nerve growth factor (NGF) in epithelial ovarian cancer

IntroductionIn many type of cancer, including epithelial ovarian cancer (EOC), nerve growth factor (NGF) and its high affinity receptor TRKA are over-expressed and also are involved in proliferation and angiogenesis. On the other hand, many inflammatory molecules such as cyclooxigenase-2 (COX-2) and prostaglandins (PGE2) are over-expressed in cancer and also involved in the progression of cancer. Besides, a deregulation of some miRs expression has been described in EOC including miR-145 among others. The relationship of NGF-mirRs-COX2 in EOC has not been studied. Then, the aim of this work was to evaluate COX-2 and miR-145 levels in EOC progression and the changes of COX-2 and miR-145 levels by NGF action in epithelial ovarian cancer cell line (A2780). Also we evaluated COX-2 levels by Western-Blot after over-expression of miR-145 in A2780 cell line.Material and methodsThirty human ovarian tissues (normal, tumour and cancer) were obtained from Obstetrics and Gynaecology Department, Clinical Hospital, University of Chile and also from National Institute of Cancer with written consent and authorised by Ethic Committee of the Institutions. The COX-2 levels in tissues and cells were measured by RT-PCR, IHQ, and Western-Blot and miR-145 was measured by qPCR. Cells A2780 were stimulated with NGF (100 and 150 ng/ml) to measure COX-2 and miR-145 levels. Besides, over-expression of miR-145 was done by transfection assays with lipofectamine-2000 to evaluate cellular invasion and also transduction assays with lenti-virus in order to evaluate COX-2 levels by Western-Blot in A2780 cell line.Results and discussionsIt was found a significant decrease of miR-145 levels in EOC tissues compared with tumour tissues and normal ovarian tissues (p<0.05). On the other hand, a significant increase of COX-2 levels was found in EOC tissues compared with tumours and normal tissues (p<0.05). The activation of TRKA receptor by NGF induced a significant decrease of miR-145 levels (p<0.05) and a significant increase of COX-2 levels (p<0.05) in epithelial ovarian cancer cell line A2780. When miR-145 was over-expressed in A2780 cells, a significant decrease of COX-2 levels was found (p<0.05). These results support the role of NGF in the regulation of miRs and inflammatory molecules in EOC.ConclusionMicroRNA-145 acts as tumour suppressor microRNA in ovarian cancer and these results suggest that miR-145 could be a good therapy for EOC.This work was supported by Grant: Fondecyt 1160139 to CR and ACCDIS - Conicyt-Fondap 15130011

MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

Ovarian carcinoma is the most lethal gynecologic tumor worldwide. Despite having developed molecular diagnostic tools and targeted therapies over the past few decades, patient survival is still quite poor. Numerous studies suggest that microRNAs are key regulators of many fundamental biological processes, including neoplasia and tumor progression. miR-222 is one of those miRNAs that has attracted much attention for its multiple roles in human diseases, especially cancer. The potential role of microRNAs in ovarian cancer has attracted much attention in recent years. Some of these microRNAs have been suggested as potential therapeutic targets for EOC patients. In this study, we sought to investigate the biologic functions of miR-222-3p in EOC carcinogenesis. Herein, we examined the expression of miR-222-3p in EOC patients, mouse models and cell lines, and found that higher expression of miR-222-3p was associated with better overall survival in EOC patients, and its level was negatively correlated with tumor growth in vivo. Furthermore, in-vitro experiments indicated that miR-222-3p inhibited EOC cell proliferation and migration, and decreased the phosphorylation of AKT. We identified GNAI2 as a target of miR-222-3p. We also found that GNAI2 promoted EOC cell proliferation, and is an activator of the PI3K/AKT pathway. We describe the characterization of a novel regulatory axis in ovarian cancer cells, miR-222-3p/GNAI2/AKT and its potential application as a therapeutic target for EOC patients.

Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis.

Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and microRNA dataset GSE47841 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using GEO2R. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape. Following, overall survival (OS) analysis of hub genes was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Moreover, miRecords was applied to predict the targets of the DEMs. A total of 345 DEGs were obtained, which were mainly enriched in the terms related to cell cycle, mitosis, and ovulation cycle process. A PPI network was constructed, consisting of 141 nodes and 296 edges. Sixteen genes had high degrees in the network. High expression of four genes of the 16 genes was associated with worse OS of patients with ovarian cancer, including CCNB1, CENPF, KIF11, and ZWINT. A significant module was detected from the PPI network. The enriched functions and pathways included cell cycle, nuclear division, and oocyte meiosis. Additionally, a total of 36 DEMs were identified. The expression of KIF11 was negatively correlated with that of has-miR-424 and has-miR-381, and it was also the potential target of two microRNAs. In conclusion, these results identified key genes, which could provide potential targets for ovarian cancer diagnosis and treatment.

492 - Functional characterization of a tumor suppressor micro-RNA in ovarian cancer

492 - Functional characterization of a tumor suppressor micro-RNA in ovarian cancer

Clinical relevance of circulating cell-free microRNAs in ovarian cancer.

Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to normalize for circulating miRNA levels, as well as differing extraction and quantification methods, are the pitfalls to be resolved before clinical application. There is still a long way, however, before this can be achieved, and further evidence would make it possible to apply circulating cell-free miRNAs not only as biomarkers but also as potential therapeutic targets for ovarian cancer in the future.

Abstract B1-20: Gene regulation by transcription factors and microRNAs in ovarian cancer

Abstract Conventional methods to analyze genomic data do not make use of the connectivity between different data types, such as transcriptional regulation and gene expression, thereby often failing to identify the cellular processes that are unique to cancer and cancer subtypes. An example of this are the four recently characterized high-grade serous ovarian cancer transcriptomic subtypes – differentiated, immunoreactive, mesenchymal, and proliferative ovarian cancer. These subtypes have not been associated with significant differences in survival, and their discovery has not lead to the identification of subtype-specific therapies. Uncovering the regulatory mechanisms mediating differences in expression between these subtypes may identify new therapeutic interventions, and ultimately help cancer patients. We modeled regulatory networks of the four ovarian cancer subtypes using PANDA, a network inference approach that uses genomic data to search for an optimal network by modeling information flow between regulators and target genes. Because not only transcription factors, but also microRNAs play an important role in gene regulation, we modified the PANDA algorithm to account for the regulatory effects of microRNAs in addition to transcription factors (miR-PANDA, in preparation). We compared the networks defining gene regulation in each subtype using different network comparison metrics. We observed a very striking pattern in out-degree differences that suggests transcription factors and microRNAs play a major role in driving the different subtypes. Using gene set enrichment analysis on in-degree differences of target genes, we identified several cancer-related pathways that are highly targeted in specific subtypes, such as regulation of Notch signaling by microRNAs in the immunoreactive subtype, and regulation of Wnt signaling by transcription factors in the proliferative subtype. These results may point to new therapeutic interventions and advance personalized treatments for ovarian cancer patients. Citation Format: Marieke Lydia Kuijjer, Kimberly Glass, John Quackenbush. Gene regulation by transcription factors and microRNAs in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-20.

MicroRNAs in Ovarian Cancer.

Ovarian cancer, consisting predominantly of ovarian carcinoma, is the eighth most common cancer in women and the most lethal gynecologic malignancy. Efforts focus on identifying biomarkers which may aid in early diagnosis and reduce mortality, as well as on characterizing therapeutic targets with the aim of circumventing chemoresistance and prolonging survival at advanced-stage disease. MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression, and have been found to play an important role in ovarian carcinoma. Recent research has identified multiple miRNAs involved in the biology and progression of the disease, and supports a role for miRNAs as potential biomarkers, predictive markers and prognostic factors. Many of the studies published to date nevertheless suffer from critical weaknesses which affect data quality and reproducibility, including the comparison of normal ovaries to tumor tissue without compensation for the highly discrepant target cell fraction in these two specimen types and the inclusion of carcinomas of different histotypes, non-epithelial tumors or tumors of non-specified histology. These shortcomings highlight the critical role of pathologists as part of the team in the setting of such research. This review summarizes current knowledge in this area and discusses the potential clinical relevance of miRNAs in ovarian carcinoma, with focus on studies of clinical specimens in which tissue selection has been deemed adequate.

Evaluation of Cell-Free Urine microRNAs Expression for the Use in Diagnosis of Ovarian and Endometrial Cancers. A Pilot Study.

Among gynaecological cancers, epithelial ovarian cancers are the most deadly cancers while endometrial cancers are the most common diseases. Efforts to establish relevant novel diagnostic, screening and prognostic markers are aimed to help reduce the high level of mortality, chemoresistance and recurrence, particularly in ovarian cancer. MicroRNAs, the class of post-transcriptional regulators, have emerged as the promising diagnostic and prognostic markers associated with various diseased states recently. Urine has been shown as the source of microRNAs several years ago; however, there has been lack of information on urine microRNA expression in ovarian and endometrial cancers till now. In this pilot study, we examined the expression of candidate cell-free urine microRNAs in ovarian cancer and endometrial cancer patients using quantitative real-time PCR. We compared the expression between pre- and post-surgery ovarian cancer samples, and between patients with ovarian and endometrial cancers and healthy controls, within three types of experiments. These experiments evaluated three different isolation methods of urine RNA, representing two supernatant and one exosome fractions of extracellular microRNA. In ovarian cancer, we found miR-92a significantly up-regulated, and miR-106b significantly down-regulated in comparison with control samples. In endometrial cancer, only miR-106b was found down-regulated significantly compared to control samples. Using exosome RNA, no significant de-regulations in microRNAs expression could be found in either of the cancers investigated. We propose that more research should now focus on confirming the diagnostic potential of urine microRNAs in gynaecological cancers using more clinical samples and large-scale expression profiling methods.

Clinically relevant microRNAs in ovarian cancer.

microRNAs (miRNAs/miRs) belong to a class of small noncoding RNAs that can negatively regulate messenger RNA (mRNA) expression of target genes. miRNAs are involved in multiple aspects of ovarian cancer cell dysfunction and the phenotype of ovarian cancer cells can be modified by targeting miRNA expression. miRNA profiling has detected a number of candidate miRNAs with the potential to regulate many important biologic functions in ovarian cancer, but their role still needs to be clarified, given the remarkable heterogeneity among ovarian cancers and the context-dependent role of miRNAs. This review summarizes the data collected from The Cancer Genome Atlas (TCGA) and several other genome-wide projects to identify dysregulated miRNAs in ovarian cancers. Copy number variations (CNVs), epigenetic alterations, and oncogenic mutations are also discussed that affect miRNA levels in ovarian disease. Emphasis is given to the role of particular miRNAs in altering expression of genes in human ovarian cancers with the potential to provide diagnostic, prognostic, and therapeutic targets. Particular attention has been given to TP53, BRCA1/2, CA125 (MUC16), HE4 (WFDC2), and imprinted genes such as ARHI (DIRAS3). A better understanding of the abnormalities in miRNA expression and downstream transcriptional and biologic consequences will provide leads for more effective biomarkers and translational approaches in the management of ovarian cancer.