microRNA and the pathogenesis of ovarian cancer – a new horizon for molecular diagnostics and treatment?

2012 ◽  
Vol 50 (4) ◽  
Author(s):  
Jan Dominik Kuhlmann ◽  
Jens Rasch ◽  
Pauline Wimberger ◽  
Sabine Kasimir-Bauer
Keyword(s):  
Ovarian Cancer ◽  
Messenger Rna ◽  
Target Genes ◽  
Mrna Translation ◽  
Ovarian Carcinomas ◽  
Rna Molecules ◽  
Sequence Complementarity ◽  
Functional Understanding ◽  
Novel Biomarkers ◽  
Gene Regulatory

AbstractOvarian cancer is the leading cause of death among gynecologic malignancies and despite advances in treatment, more than 50% of all patients will experience recurrence, resulting in worse overall prognosis. Therefore, identification of novel biomarkers for ovarian cancer is of significant interest. microRNA (miRNA) constitute a class of small gene regulatory RNA molecules (18–24 nt) and by sequence complementarity, they negatively regulate messenger RNA (mRNA) translation of target genes. Rising data are available that miRNA are functionally involved in the pathogenesis of ovarian cancer. In this regard, recent advances in profiling studies revealed a variety of miRNA candidates, differently expressed in ovarian carcinomas and in disease-specific conditions like hypoxia or chemo-resistance. This review abstracts recent efforts on establishing miRNA as novel molecular biomarkers for ovarian cancer and depicts the existing preliminary framework for defining peripheral-blood derived miRNA as novel circulating biomarkers. Beside these clinical implications, we highlight the current functional understanding of miRNA alteration and discuss major challenges in miRNA profiling approaches. Finally, we briefly outline methodologies to therapeutically modulate miRNA expression in cancer and try to assess how miRNA can improve our conceptual understanding and the clinical management of ovarian cancer.

scholarly journals Identifying Differentially Expressed MicroRNAs, Target Genes, and Key Pathways Deregulated in Patients with Liver Diseases

2020 ◽  
Vol 21 (19) ◽  
pp. 7368
Author(s):  
Maryam Gholizadeh ◽  
Sylwia Szelag-Pieniek ◽  
Mariola Post ◽  
Mateusz Kurzawski ◽  
Jesus Prieto ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Liver Diseases ◽  
Target Genes ◽  
Topological Analysis ◽  
Mirna Gene ◽  
Mrna Translation ◽  
Differentially Expressed ◽  
Microrna Target ◽  
Disease Etiology ◽  
Key Pathways

Liver diseases are important causes of morbidity and mortality worldwide. The aim of this study was to identify differentially expressed microRNAs (miRNAs), target genes, and key pathways as innovative diagnostic biomarkers in liver patients with different pathology and functional state. We determined, using RT-qPCR, the expression of 472 miRNAs in 125 explanted livers from subjects with six different liver pathologies and from control livers. ANOVA was employed to obtain differentially expressed miRNAs (DEMs), and miRDB (MicroRNA target prediction database) was used to predict target genes. A miRNA–gene differential regulatory (MGDR) network was constructed for each condition. Key miRNAs were detected using topological analysis. Enrichment analysis for DEMs was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We identified important DEMs common and specific to the different patient groups and disease progression stages. hsa-miR-1275 was universally downregulated regardless the disease etiology and stage, while hsa-let-7a*, hsa-miR-195, hsa-miR-374, and hsa-miR-378 were deregulated. The most significantly enriched pathways of target genes controlled by these miRNAs comprise p53 tumor suppressor protein (TP53)-regulated metabolic genes, and those involved in regulation of methyl-CpG-binding protein 2 (MECP2) expression, phosphatase and tensin homolog (PTEN) messenger RNA (mRNA) translation and copper homeostasis. Our findings show a novel panel of deregulated miRNAs in the liver tissue from patients with different liver pathologies. These miRNAs hold potential as biomarkers for diagnosis and staging of liver diseases.

scholarly journals Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255142
Author(s):  
Joanna Lopacinska-Jørgensen ◽  
Douglas V. N. P. Oliveira ◽  
Guy Wayne Novotny ◽  
Claus K. Høgdall ◽  
Estrid V. Høgdall
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Messenger Rna ◽  
Clear Cell ◽  
Expression Patterns ◽  
Target Prediction ◽  
Aberrant Expression ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Microarray Profiling

Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.

Claudin-7 expression in human epithelial ovarian cancer

2008 ◽  
Vol 18 (6) ◽  
pp. 1262-1271 ◽  
Author(s):  
R. A. Tassi ◽  
E. Bignotti ◽  
M. Falchetti ◽  
M. Ravanini ◽  
S. Calza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peritoneal Cavity ◽  
Protein Level ◽  
Messenger Rna ◽  
Inflammatory Cells ◽  
Surface Epithelium ◽  
Ovarian Adenocarcinoma ◽  
Ovarian Carcinomas ◽  
Junction Protein ◽  
Histologic Types

Claudin-7 (CLDN-7) is a tight junction protein recently found highly differentially expressed in ovarian carcinoma. To evaluate its potential as a novel biomarker, in this study, we quantified and compared claudin-7 expression at messenger RNA and protein level in 110 patients harboring various histologic types of epithelial ovarian carcinomas (EOC). CLDN-7 transcript was found significantly overexpressed in both primary and metastatic EOCs compared to normal human ovarian surface epithelium cell lines (fold change = 111.4, P< 0.001) by reverse transcription–polymerase chain reaction. At the protein level, CLDN-7 expression was found significantly higher in tumors of primary and metastatic origin when compared to normal ovaries (P< 0.001), regardless of the histologic type, the grade of differentiation, and the pathologic stage of the disease (P= 0.12). Moreover, a strong immunoreactivity for CLDN-7 was detected in EOC cells present in ascites fluids, whereas ascites-derived inflammatory cells, histiocytes, and reactive mesothelial cells were negative. Finally, immunohistochemical expression of CLDN-7 was observed in several human normal epithelial control tissues analyzed. CLDN-7 is significantly overexpressed in all main histologic types of EOC and in single neoplastic cells disseminated in peritoneal cavity and pleural effusions, suggesting its potential role as novel diagnostic marker in ovarian cancer. Despite widespread expression of CLDN-7 in several human normal tissues, the high density of CLDN-7 molecules, their membranous localization on EOC cells, and their lack of expression on the celomic epithelium in the peritoneal cavity suggest that this target could be potentially suitable for antibody-mediated localized therapies of ovarian adenocarcinoma.

scholarly journals Increased hippocampal excitability in miR-324-null mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan J. Hayman ◽  
Tamara Modebadze ◽  
Sarah Charlton ◽  
Kat Cheung ◽  
Jamie Soul ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Target Genes ◽  
Translational Repression ◽  
Rna Molecules ◽  
Rna Transcripts ◽  
Gene Transcripts ◽  
Non Coding Rnas ◽  
Interictal Discharges ◽  
The Brain

AbstractMicroRNAs are non-coding RNAs that act to downregulate the expression of target genes by translational repression and degradation of messenger RNA molecules. Individual microRNAs have the ability to specifically target a wide array of gene transcripts, therefore allowing each microRNA to play key roles in multiple biological pathways. miR-324 is a microRNA predicted to target thousands of RNA transcripts and is expressed far more highly in the brain than in any other tissue, suggesting that it may play a role in one or multiple neurological pathways. Here we present data from the first global miR-324-null mice, in which increased excitability and interictal discharges were identified in vitro in the hippocampus. RNA sequencing was used to identify differentially expressed genes in miR-324-null mice which may contribute to this increased hippocampal excitability, and 3′UTR luciferase assays and western blotting revealed that two of these, Suox and Cd300lf, are novel direct targets of miR-324. Characterisation of microRNAs that produce an effect on neurological activity, such as miR-324, and identification of the pathways they regulate will allow a better understanding of the processes involved in normal neurological function and in turn may present novel pharmaceutical targets in treating neurological disease.

scholarly journals BCL7C suppresses ovarian cancer growth by inactivating mutant p53

2020 ◽  
Author(s):  
Canhua Huang ◽  
Qian Hao ◽  
Getao Shi ◽  
Xiang Zhou ◽  
Yu Zhang
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Target Genes ◽  
Ovarian Cancer Cells ◽  
Mutant P53 ◽  
Ovarian Carcinomas ◽  
Ovarian Tumorigenesis ◽  
P53 Target Genes ◽  
Proliferation And Invasion

Abstract B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. Here, we report our finding of its tumor-suppressive role in ovarian cancer. Supporting this is that BCL7C is downregulated in human ovarian carcinomas, and its underexpression is associated with unfavorable prognosis of ovarian cancer as well as some other types of human cancers. Also, ectopic BCL7C restrains cell proliferation and invasion of ovarian cancer cells. Consistently, depletion of BCL7C reduces apoptosis and promotes cell proliferation and invasion of these cancer cells. Mechanistically, BCL7C suppresses mutant p53-mediated gene transcription by binding to mutant p53, while knockdown of BCL7C enhances the expression of mutant p53 target genes in ovarian cancer cells. Primary ovarian carcinomas that sustain low levels of BCL7C often show the elevated expression of mutant p53 target genes. In line with these results, BCL7C abrogates mutant p53-induced cell proliferation and invasion, but had no impact on proliferation and invasion of cancer cells with depleted p53 or harboring wild-type p53. Altogether, our results demonstrate that BCL7C can act as a tumor suppressor to prevent ovarian tumorigenesis and progression by counteracting mutant p53 activity.

scholarly journals Ubiquitin ligase TRIM71 suppresses ovarian tumorigenesis by degrading mutant p53

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Yajie Chen ◽  
Qian Hao ◽  
Jieqiong Wang ◽  
Jiajia Li ◽  
Canhua Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ubiquitin Ligase ◽  
Target Genes ◽  
Mutant P53 ◽  
Cancer Cell Proliferation ◽  
Ovarian Carcinomas ◽  
Ovarian Tumorigenesis ◽  
P53 Target Genes

Abstract Hotspot p53 mutants augment cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Ovarian cancer sustains the highest frequency of TP53 mutations, but the mechanisms underlying regulation of mutant p53s’ GOF in this type of cancer remain incompletely understood. Herein, we identified the E3-ubiquitin ligase TRIM71 as a novel mutant p53-binding protein. Ectopic TRIM71-induced ubiquitination and proteasomal degradation of mutant p53 by binding to its transactivation (TA) domain, and inhibited the expression of a broad spectrum of mutant p53 target genes. Ectopic TRIM71 also restrained, whereas ablation of TRIM71 endorsed, ovarian carcinoma cell growth in vitro and in vivo. Significantly, TRIM71 overexpression is highly associated with favorable prognosis, particularly, in TP53-mutated ovarian carcinomas. Altogether, our findings unveil the anti-tumor function of TRIM71 in ovarian cancer development and prognosis by downregulating mutant p53s.

scholarly journals MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
E. Krasniqi ◽  
A. Sacconi ◽  
D. Marinelli ◽  
L. Pizzuti ◽  
M. Mazzotta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Target Genes ◽  
Ovarian Tissue ◽  
Gynecological Cancer ◽  
Enrichment Analysis ◽  
Platinum Resistance ◽  
Tissue Samples ◽  
Ribonucleic Acids ◽  
Survival Endpoints ◽  
Novel Biomarkers

Abstract Background In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. Methods We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). Results In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. Conclusions Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

MOLECULAR AND GENETIC SUBTYPES OF OVARIAN CANCER: PROSPECTS FOR FURTHER STUDIES

2019 ◽  
Vol 65 (1) ◽  
pp. 56-62
Author(s):  
Alisa Villert ◽  
Larisa Kolomiets ◽  
Natalya Yunusova ◽  
Yevgeniya Fesik
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Molecular Subtypes ◽  
Survival Rates ◽  
Consensus Algorithm ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Genetic Subtypes

High-grade ovarian carcinoma is a histopathological diagnosis, however, at the molecular level, ovarian cancer represents a heterogeneous group of diseases. Studies aimed at identifying molecular genetic subtypes of ovarian cancer are conducted in order to find the answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements in this trend is the recognition of the dualistic model that categorizes various types of ovarian cancer into two groups designated high-grade (HG) and low-grade (LG) tumors. However, the tumor genome sequencing data suggest the existence of 6 ovarian carcinoma subtypes, including two LG and four HG subtypes. Subtype C1 exhibits a high stromal response and the lowest survival. Subtypes C2 and C4 demonstrate higher number of intratumoral CD3 + cells, lower stromal gene expression and better survival than sybtype C1. Subtype C5 (mesenchymal) is characterized by mesenchymal cells, over-expression of N-cadherin and P-cadherin, low expression of differentiation markers, and lower survival rates than C2 and C4. The use of a consensus algorithm to determine the subtype allows identification of only a minority of ovarian carcinomas (approximately 25%) therefore, the practical importance of this classification requires additional research. There is evidence that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and groups with overexpression of the immune response genes, as in the angiogenic group there is a comparative superiority in terms of survival. The administration of bevacizumab in the angiogenic group improves survival, while the administration of bevacizumab in the immune group even worsens the outcome. Molecular subtypes with worse survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. This review focuses on some of the advances in understanding molecular, cellular, and genetic changes in ovarian carcinomas with the results achieved so far regarding the formulation of molecular subtypes of ovarian cancer, however further studies are needed.

Ovarian Cancer: Differentially Expressed microRNAs in Tumor Tissue and Cell-Free Ascitic Fluid as Potential Novel Biomarkers

2019 ◽  
Vol 37 (9) ◽  
pp. 440-452 ◽  
Author(s):  
Luděk Záveský ◽  
Eva Jandáková ◽  
Vít Weinberger ◽  
Luboš Minář ◽  
Veronika Hanzíková ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ascitic Fluid ◽  
Tumor Tissue ◽  
Differentially Expressed ◽  
Novel Biomarkers

scholarly journals MiR-200c-3p Contrasts PD-L1 Induction by Combinatorial Therapies and Slows Proliferation of Epithelial Ovarian Cancer through Downregulation of β-Catenin and c-Myc

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 519
Author(s):  
Eleni Anastasiadou ◽  
Elena Messina ◽  
Tiziana Sanavia ◽  
Lucia Mundo ◽  
Federica Farinella ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Ovarian Cancer Cells ◽  
Oncogenic Signaling ◽  
Experimental Conditions ◽  
Skov3 Cells ◽  
In Silico Analyses ◽  
Post Therapy

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients’ biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC.

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