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      Diagnostic and Prognostic Potential of MicroRNA Maturation Regulators Drosha, AGO1 and AGO2 in Urothelial Carcinomas of the Bladder

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          Abstract

          Bladder cancer still requires improvements in diagnosis and prognosis, because many of the cases will recur and/or metastasize with bad outcomes. Despite ongoing research on bladder biomarkers, the clinicopathological impact and diagnostic function of miRNA maturation regulators Drosha and Argonaute proteins AGO1 and AGO2 in urothelial bladder carcinoma remain unclear. Therefore, we conducted immunohistochemical investigations of a tissue microarray composed of 112 urothelial bladder carcinomas from therapy-naïve patients who underwent radical cystectomy or transurethral resection and compared the staining signal with adjacent normal bladder tissue. The correlations of protein expression of Drosha, AGO1 and AGO2 with sex, age, tumor stage, histological grading and overall survival were evaluated in order to identify their diagnostic and prognostic potential in urothelial cancer. Our results show an upregulation of AGO1, AGO2 and Drosha in non-muscle-invasive bladder carcinomas, while there was increased protein expression of only AGO2 in muscle-invasive bladder carcinomas. Moreover, we were able to differentiate between non-muscle-invasive and muscle-invasive bladder carcinoma according to AGO1 and Drosha expression. Finally, despite Drosha being a discriminating factor that can predict the probability of overall survival in the Kaplan–Meier analysis, AGO1 turned out to be independent of all clinicopathological parameters according to Cox regression. In conclusion, we assumed that the miRNA processing factors have clinical relevance as potential diagnostic and prognostic tools for bladder cancer.

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          Most cited references22

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          Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration

          The REMARK “elaboration and explanation” guideline, by Doug Altman and colleagues, provides a detailed reference for authors on important issues to consider when designing, conducting, and analyzing tumor marker prognostic studies.
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            EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update.

            To present the 2011 European Association of Urology (EAU) guidelines on non-muscle-invasive bladder cancer (NMIBC). Literature published between 2004 and 2010 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the level of evidence (LE) and grade of recommendation (GR) were assigned. Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2-6 wk. In papillary tumours, the risks of both recurrence and progression may be estimated for individual patients using the scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups-separately for recurrence and progression-is pivotal to recommending adjuvant treatment. For patients with a low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is recommended. Patients with an intermediate or high risk of recurrence and an intermediate risk of progression should receive one immediate instillation of chemotherapy followed by a minimum of 1 yr of bacillus Calmette-Guérin (BCG) intravesical immunotherapy or further instillations of chemotherapy. Papillary tumours with a high risk of progression and CIS should receive intravesical BCG for 1 yr. Cystectomy may be offered to the highest risk patients, and it is at least recommended in BCG failure patients. The long version of the guidelines is available from the EAU Web site (www.uroweb.org). These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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              High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.

              MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                31 May 2018
                June 2018
                : 19
                : 6
                : 1622
                Affiliations
                [1 ]Department of Urology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; n.ratert@ 123456gmx.de (N.R.); klaus.jung@ 123456charite.de (K.J.)
                [2 ]Berlin Institute for Urologic Research, 10117 Berlin, Germany
                [3 ]Institute of Pathology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; anica.hoegner@ 123456charite.de (A.H.); e.kilic@ 123456pathologie-leverkusen.de (E.K.)
                [4 ]Institute of Pathology, University Medicine Rostock, 18055 Rostock, Germany; andreas.erbersdobler@ 123456med.uni-rostock.de
                [5 ]Department of Urology, HELIOS Hospital Bad Saarow, 15526 Bad Saarow, Germany; thorsten.ecke@ 123456helios-kliniken.de
                [6 ]Institute of Pathology, Hospital Leverkusen, 51375 Leverkusen, Germany
                Author notes
                [* ]Correspondence: anja.rabien@ 123456charite.de ; Tel.: +49-30-450515035; Fax: +49-30-450515904
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-0787-2763
                Article
                ijms-19-01622
                10.3390/ijms19061622
                6032056
                29857476
                030d0c07-8307-4a54-a5c1-1ca2e2bac217
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 May 2018
                : 30 May 2018
                Categories
                Article

                Molecular biology
                bladder cancer,drosha,ago1,ago2,biomarkers,immunohistochemistry
                Molecular biology
                bladder cancer, drosha, ago1, ago2, biomarkers, immunohistochemistry

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