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      Circulating mRNAs and miRNAs as candidate markers for the diagnosis and prognosis of prostate cancer

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          Abstract

          Circulating nucleic acids are found in free form in body fluids and may serve as minimally invasive tools for cancer diagnosis and prognosis. Only a few studies have investigated the potential application of circulating mRNAs and microRNAs (miRNAs) in prostate cancer (PCa). The Cancer Genome Atlas (TCGA) database was used for an in silico analysis to identify circulating mRNA and miRNA as potential markers of PCa. A total of 2,267 genes and 49 miRNAs were differentially expressed between normal and tumor samples. The prediction analyses of target genes and integrative analysis of mRNA and miRNA expression revealed eleven genes and eight miRNAs which were validated by RT-qPCR in plasma samples from 102 untreated PCa patients and 50 cancer-free individuals. Two genes, OR51E2 and SIM2, and two miRNAs, miR-200c and miR-200b, showed significant association with PCa. Expression levels of these transcripts distinguished PCa patients from controls (67% sensitivity and 75% specificity). PCa patients and controls with prostate-specific antigen (PSA) ≤ 4.0 ng/mL were discriminated based on OR51E2 and SIM2 expression levels. The miR-200c expression showed association with Gleason score and miR-200b, with bone metastasis, bilateral tumor, and PSA > 10.0 ng/mL. The combination of circulating mRNA and miRNA was useful for the diagnosis and prognosis of PCa.

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          Most cited references39

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          miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database

          MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides, which negatively regulate the gene expression at the post-transcriptional level. This study describes an update of the miRTarBase (http://miRTarBase.mbc.nctu.edu.tw/) that provides information about experimentally validated miRNA-target interactions (MTIs). The latest update of the miRTarBase expanded it to identify systematically Argonaute-miRNA-RNA interactions from 138 crosslinking and immunoprecipitation sequencing (CLIP-seq) data sets that were generated by 21 independent studies. The database contains 4966 articles, 7439 strongly validated MTIs (using reporter assays or western blots) and 348 007 MTIs from CLIP-seq. The number of MTIs in the miRTarBase has increased around 7-fold since the 2014 miRTarBase update. The miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) are integrated to provide an effective overview of this exponential growth in the miRNA experimental data. These improvements make the miRTarBase one of the more comprehensively annotated, experimentally validated miRNA-target interactions databases and motivate additional miRNA research efforts.
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            Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.

            The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter. Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range. Copyright 2004 Massachusetts Medical Society
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              Molecular genetics of prostate cancer: new prospects for old challenges.

              Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 September 2017
                2017
                : 12
                : 9
                : e0184094
                Affiliations
                [1 ] General Biology Department, State University of Londrina, Londrina, Paraná, Brazil
                [2 ] CIPE, AC Camargo Cancer Center, São Paulo, São Paulo, Brazil
                [3 ] Londrina Cancer Hospital, Londrina, Paraná, Brazil
                [4 ] Department of Computing, Federal University of Technology—Paraná, UTFPR, Cornélio Procópio, Paraná, Brazil
                [5 ] Department of Clinical Genetics, Vejle Hospital and Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-20570
                10.1371/journal.pone.0184094
                5598937
                28910345
                88b20ac2-2d76-4b7f-85bc-90851a65c454
                © 2017 Souza et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 May 2017
                : 17 August 2017
                Page count
                Figures: 4, Tables: 3, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004612, Fundação Araucária;
                Award ID: 185/2014
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2008/57887-9
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 573589/08-9
                Award Recipient :
                This study was supported by grants from the Araucaria Foundation of Support for the Scientific and Technological of Paraná (185/2014), National Institute of Science and Technology in Oncogenomics (Sao Paulo Research Foundation FAPESP 2008/57887-9 and Brazilian National Council for Scientific and Technological Development CNPq 573589/08-9), Coordination for the Improvement of Higher Education Personnel Brazil (CAPES), Brazil and Vejle Hospital, Institute of Regional Health Research, Vejle, Denmark (K16-04V). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Medicine and Health Sciences
                Urology
                Prostate Diseases
                Prostate Cancer
                Biology and life sciences
                Genetics
                Gene expression
                Gene regulation
                MicroRNAs
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                MicroRNAs
                Medicine and Health Sciences
                Diagnostic Medicine
                Cancer Detection and Diagnosis
                Medicine and Health Sciences
                Oncology
                Cancer Detection and Diagnosis
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Messenger RNA
                Medicine and Health Sciences
                Oncology
                Metastasis
                Medicine and Health Sciences
                Oncology
                Basic Cancer Research
                Metastasis
                Medicine and Health Sciences
                Diagnostic Medicine
                Prognosis
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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