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      Functional Long Noncoding RNAs (lncRNAs) in Clear Cell Kidney Carcinoma Revealed by Reconstruction and Comprehensive Analysis of the lncRNA–miRNA–mRNA Regulatory Network

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          Abstract

          Background

          A variety of treatment strategies have been developed for clear cell kidney carcinoma (KIRC); however, there is still a need for effective therapeutic targets and prognostic molecular biomarkers. Given that long noncoding RNAs (lncRNAs) has been emerging as an important regulator in tumorigenesis, we explored potential functional lncRNAs in KIRC by comprehensively analyzing the lncRNA–miRNA–mRNA regulatory network with bioinformatics processing tools.

          Material/Methods

          RNA-seq/miRNA-seq data of KIRC in The Cancer Genome Atlas (TCGA) were obtained and analyzed. The “edgeR” package in R software was used to identify differentially expressed lncRNAs (DElncRNAs, differentially expressed long noncoding RNAs), miRNAs (DEmiRNAs, differentially expressed micro RNAs), and mRNAs (DEmRNAs, differentially expressed messenger RNAs) in KIRC and normal samples. A global triple network was conducted based on the competing endogenous RNA (ceRNA) theory, and survival analysis was conducted by “survival” package in R software.

          Results

          A total of 4246 DElncRNAs, 179 DEmiRNAs, and 5758 DEmRNAs were identified, among which a subset of them (321 lncRNAs, 26 miRNAs, and 1068 mRNAs) were found to constitute a global ceRNA network in KIRC. Four lncRNAs (ENTPD3-AS1, FGD5-AS1, LIFR-AS1, and UBAC2-AS1) were revealed to be potential therapeutic targets as well as prognostic biomarkers of KIRC by our extensive functional analysis.

          Conclusions

          We reported here the identification of functional lncRNAs in KIRC via a TCGA data-based bioinformatics analysis. We believe that this study might contribute to improving the comprehension of the lncRNA-mediated ceRNA regulatory mechanisms in the tumorigenesis of KIRC. Meanwhile, our results suggested that 4 lncRNAs might act as potential therapeutic targets or candidate prognostic biomarkers in KIRC.

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          Most cited references33

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          Divergent lncRNAs Regulate Gene Expression and Lineage Differentiation in Pluripotent Cells.

          Divergent lncRNAs that are transcribed in the opposite direction to nearby protein-coding genes comprise a significant proportion (∼20%) of total lncRNAs in mammalian genomes. Through genome-wide analysis, we found that the distribution of this lncRNA class strongly correlates with essential developmental regulatory genes. In pluripotent cells, divergent lncRNAs regulate the transcription of nearby genes. As an example, the divergent lncRNA Evx1as promotes transcription of its neighbor gene, EVX1, and regulates mesendodermal differentiation. At a single-cell level, early broad expression of Evx1as is followed by a rapid, high-level transcription of EVX1, supporting the idea that Evx1as plays an upstream role to facilitate EVX1 transcription. Mechanistically, Evx1as RNA binds to regulatory sites on chromatin, promotes an active chromatin state, and interacts with Mediator. Based on our analyses, we propose that the biological function of thousands of uncharacterized lncRNAs of this class may be inferred from the role of their neighboring adjacent genes.
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            Molecular genetics of clear-cell renal cell carcinoma.

            Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.
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              The ways of action of long non-coding RNAs in cytoplasm and nucleus.

              Over the past fifteen years, small regulatory RNAs, such as siRNA and miRNA, have been extensively investigated and the underlying molecular mechanisms have been well documented, suggesting that ncRNAs play a major function in many cellular processes. An expanding body of evidence reveals that long non-coding RNAs (lncRNAs), once described as dark matter, are involved in diverse cellular progresses, including regulation of gene expression, dosage compensation, genomic imprinting, nuclear organization and nuclear-cytoplasm trafficking via a number of complex mechanisms. The emerging links between lncRNAs and diseases as well as their tissue-specific expression patterns also indicate that lncRNAs comprise a core transcriptional regulatory circuitry. The function of lncRNAs is based on their sequence and structure; and they can combine with DNA, RNA, and proteins both in the nucleus and the cytoplasm. However, detailed insights into their biological and mechanistic functions are only beginning to emerge. In this review, we will mainly talk about diverse ways of action of lncRNAs in different sub-cellular locations and provide clues for following studies. Copyright © 2014 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2018
                16 November 2018
                : 24
                : 8250-8263
                Affiliations
                Fujian Provincial Key Laboratory of Transplant Biology, Department of Urology, Fuzhou Dongfang Hospital, Xiamen University, Fuzhou, Fujian, P.R. China
                Author notes
                Corresponding Authors: Jianming Tan, e-mail: tanjm156@ 123456xmu.edu.cn ; Jun Lu, e-mail: junlu.heather@ 123456xmu.edu.cn
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                These authors equally contribute to this paper

                Article
                910773
                10.12659/MSM.910773
                6251074
                30444862
                1f7d0964-f6e3-437b-be82-cd06ba12a8b5
                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 24 April 2018
                : 21 July 2018
                Categories
                Lab/In Vitro Research

                carcinoma, renal cell,micrornas,rna, long noncoding
                carcinoma, renal cell, micrornas, rna, long noncoding

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