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      Long Non-coding RNAs Involved in Resistance to Chemotherapy in Ovarian Cancer

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          Ovarian cancer (OC) accounts for more than 150,000 deaths worldwide every year. Patients are often diagnosed at an advanced stage with metastatic dissemination. Although platinum- and taxane-based chemotherapies are effective treatment options, they are rarely curative and eventually, the disease will progress due to acquired resistance. Emerging evidence suggests a crucial role of long non-coding RNAs (lncRNAs) in the response to therapy in OC. Transcriptome profiling studies using high throughput approaches have identified differential expression patterns of lncRNAs associated with disease recurrence. Furthermore, several aberrantly expressed lncRNAs in resistant OC cells have been related to increased cell division, improved DNA repair, up-regulation of drug transporters or reduced susceptibility to apoptotic stimuli, supporting their involvement in acquired resistance. In this review, we will discuss the key aspects of lncRNAs associated with the development of resistance to platinum- and taxane-based chemotherapy in OC. The molecular landscape of OC will be introduced, to provide a background for understanding the role of lncRNAs in the acquisition of malignant properties. We will focus on the interplay between lncRNAs and molecular pathways affecting drug response to evaluate their impact on treatment resistance. Additionally, we will discuss the prospects of using lncRNAs as biomarkers or targets for precision medicine in OC. Although there is still plenty to learn about lncRNAs and technical challenges to be solved, the evidence of their involvement in OC and the development of acquired resistance are compelling and warrant further investigation for clinical applications.

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          Most cited references 193

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          Integrated Genomic Analyses of Ovarian Carcinoma

          Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.
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            Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

            Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome1, 2, 3 yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities6,7,8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
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              The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.

              The human genome contains many thousands of long noncoding RNAs (lncRNAs). While several studies have demonstrated compelling biological and disease roles for individual examples, analytical and experimental approaches to investigate these genes have been hampered by the lack of comprehensive lncRNA annotation. Here, we present and analyze the most complete human lncRNA annotation to date, produced by the GENCODE consortium within the framework of the ENCODE project and comprising 9277 manually annotated genes producing 14,880 transcripts. Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts, they are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Importantly, about one-third seem to have arisen within the primate lineage. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. This GENCODE annotation represents a valuable resource for future studies of lncRNAs.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                21 January 2020
                : 9
                1Department of Clinical Genetics, Lillebaelt Hospital-University Hospital of Southern Denmark , Vejle, Denmark
                2Department of Clinical Oncology, Lillebaelt Hospital-University Hospital of Southern Denmark , Vejle, Denmark
                3Institute of Regional Health Research, University of Southern Denmark , Odense, Denmark
                Author notes

                Edited by: Deilson Elgui De Oliveira, São Paulo State University, Brazil

                Reviewed by: Monica Montopoli, University of Padova, Italy; Raphael Carmo Valente, Rio de Janeiro State University, Brazil

                *Correspondence: Silvia R. Rogatto silvia.regina.rogatto@

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Copyright © 2020 Abildgaard, Do Canto, Steffensen and Rogatto.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 196, Pages: 17, Words: 13434

                Oncology & Radiotherapy

                precision medicine, chemotherapy, drug resistance, lncrna, ovarian cancer


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