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      Potential Five-MicroRNA Signature Model for the Prediction of Prognosis in Patients with Wilms Tumor

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          Abstract

          Background

          Wilms tumor (WT) is the most common type of pediatric renal malignancy, and is associated with poor prognosis. The aim of the present study was to identify microRNA (miRNA) signatures which might predict prognosis and categorize WTs into high- and low-risk subgroups.

          Material/Methods

          The miRNA expression profiles of WT patients and normal samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment database. Differentially expressed miRNAs between WT patients and normal samples were identified using the EdgeR package. Subsequently, correlations between differentially expressed miRNAs and the prognosis of overall survival were analyzed. Enrichment analyses for the targeted mRNAs were conducted via the Database for Annotation, Visualization, and Integration Discovery.

          Results

          A total of 154 miRNAs were identified as differentially expressed in WT. Of those, 18 miRNAs were associated with overall survival ( P<0.05). A prognostic signature of 5 differentially expressed miRNAs (i.e., has-mir-149, has-mir-7112, has-mir-940, has-mir-1248, and has-mir-490) was constructed to classify the patients into high- and low-risk subgroups. The targeted mRNAs of these prognostic miRNAs were primarily enriched in Gene Ontology terms (i.e., protein autophosphorylation, protein dephosphorylation, and stress-activated MAPK cascade) and the Kyoto Encyclopedia of Genes and Genomes signaling pathways (i.e., MAPK, AMPK, and PI3K-Akt).

          Conclusions

          The 5-miRNA signature model might be useful in determining the prognosis of WT patients. As a promising prediction tool, this prognosis signature might serve as a potential biomarker for WT patients.

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          Most cited references28

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          miRDB: an online resource for microRNA target prediction and functional annotations

          MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in many physiological and disease processes. One major challenge in miRNA studies is the identification of genes regulated by miRNAs. To this end, we have developed an online resource, miRDB (http://mirdb.org), for miRNA target prediction and functional annotations. Here, we describe recently updated features of miRDB, including 2.1 million predicted gene targets regulated by 6709 miRNAs. In addition to presenting precompiled prediction data, a new feature is the web server interface that allows submission of user-provided sequences for miRNA target prediction. In this way, users have the flexibility to study any custom miRNAs or target genes of interest. Another major update of miRDB is related to functional miRNA annotations. Although thousands of miRNAs have been identified, many of the reported miRNAs are not likely to play active functional roles or may even have been falsely identified as miRNAs from high-throughput studies. To address this issue, we have performed combined computational analyses and literature mining, and identified 568 and 452 functional miRNAs in humans and mice, respectively. These miRNAs, as well as associated functional annotations, are presented in the FuncMir Collection in miRDB.
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            Oncogenic role of miR-483-3p at the IGF2/483 locus.

            hsa-mir-483 is located within intron 2 of the IGF2 locus. We found that the mature microRNA (miRNA) miR-483-3p is overexpressed in 100% of Wilms' tumors. In addition, colon, breast, and liver cancers exhibit high or even extremely high levels of miR-483-3p in approximately 30% of the cases. A coregulation with IGF2 mRNA was detected, although some tumors exhibited high expression of miR-483-3p without a concomitant increase of IGF2. These findings suggested that miR-483-3p could cooperate with IGF2 or act as an autonomous oncogene. Indeed, here we prove that an anti-miRNA oligonucleotide against miR-483-3p could inhibit the miRNAs without affecting IGF2 mRNA and it could suppress tumorigenicity of HepG2 cells, a cell line that overexpresses miR-483-3p and IGF2. Conversely, no antitumor effect was elicited by inhibition of IGF2. The oncogenic mechanism of miR-483-3p was at least partially clarified by the finding that it could modulate the proapoptotic protein BBC3/PUMA and miR-483-3p enforced expression could protect cells from apoptosis. Our results indicate that miR-483-3p could function as an antiapoptotic oncogene in various human cancers and reveal a new, potentially important target for anticancer therapy. (c) 2010 AACR.
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              The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis

              Insulin-like growth factor 2 (IGF2) is frequently overexpressed in pediatric cancers. In a miRNA screen of primary Wilms' tumors, Haber and colleagues identify specific overexpression of miR-483-5p, which is embedded in the IGF2 gene. Interestingly, the IGF2 mRNA itself is transcriptionally up-regulated by miR-483-5p. A nuclear pool of miR-483-5p binds the IGF2 mRNA, enhancing the association of RNA helicase and promoting IGF2 transcription. This unexpected nuclear function for a miRNA points to the complexity of mechanisms regulating IGF2 expression, implicated in both normal development and cancer.
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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
                2019
                22 July 2019
                : 25
                : 5435-5444
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, P.R. China
                [2 ]Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, P.R. China
                Author notes
                Corresponding Author: Jian Li, e-mail: lijian5@ 123456mail.sysu.edu.cn
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                Yihang Gong, Baojia Zou and Jianxu Chen contributed equally to this research

                Article
                916230
                10.12659/MSM.916230
                6668497
                31328722
                d0b5c30f-e2b6-4ff0-b89a-2f4a621e8143
                © Med Sci Monit, 2019

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

                History
                : 14 March 2019
                : 06 June 2019
                Categories
                Clinical Research

                micrornas,prognosis,wilms tumor
                micrornas, prognosis, wilms tumor

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