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      Pre-Micro RNA Signatures Delineate Stages of Endothelial Cell Transformation in Kaposi Sarcoma

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          Abstract

          MicroRNAs (miRNA) have emerged as key regulators of cell lineage differentiation and cancer. We used precursor miRNA profiling by a novel real-time QPCR method (i) to define progressive stages of endothelial cell transformation cumulating in Kaposi sarcoma (KS) and (ii) to identify specific miRNAs that serve as biomarkers for tumor progression. We were able to compare primary patient biopsies to well-established culture and mouse tumor models. Loss of mir-221 and gain of mir-15 expression demarked the transition from merely immortalized to fully tumorigenic endothelial cells. Mir-140 and Kaposi sarcoma–associated herpesvirus viral miRNAs increased linearly with the degree of transformation. Mir-24 emerged as a biomarker specific for KS.

          Author Summary

          MicroRNAs are key regulators of cancer and development. We can use their pattern of expression to classify different cancers or in our case different stages in cancer development. We used a novel method to define progressive stages for Kaposi sarcoma (KS), which is a cancer of the endothelial cells. We identified specific precursor-miRNAs that accurately identify stages of KS tumor progression. For the first time, we were able to profile KS patient material. This is difficult to come by, but it is more closely related to the human cancer than even the best cell culture models. Our work statistically defined clusters of pre-miRNAs, each signifying one step in cancer progression. This is the first time that precursor miRNAs profiling was used to define cancer stages. It is also the first time that we have defined makers of any kind that allow us to distinguish between different types of the endothelial cancer KS. Loss of mir-221 precursor miRNA and gain of mir-15 precursor miRNA expression demarked the transition from merely immortal to fully tumorigenic cells. Mir-140 and Kaposi sarcoma–associated herpesvirus viral microRNAs increased progressively with the degree of transformation, i.e. more aggressive stages expressed higher levels of these biomarkers. High levels of the precursor microRNA mir-24 emerged as a biomarker only in patient derived KS samples, not in any of the culture models.

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          Most cited references71

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          Cluster analysis and display of genome-wide expression patterns.

          A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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            A genetic model for colorectal tumorigenesis.

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              Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

              Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                April 2009
                April 2009
                17 April 2009
                : 5
                : 4
                : e1000389
                Affiliations
                [1 ]Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, Center for AIDS Research at the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [2 ]Federal University of Bahia, Salvador, Bahia, Brazil
                [3 ]The Viral Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [4 ]Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
                Oregon Health and Science University, United States of America
                Author notes

                Conceived and designed the experiments: WJH BD. Performed the experiments: AJO PC LW EL. Analyzed the data: DPD AJO BD. Contributed reagents/materials/analysis tools: PC LW EMN EL WJH BJD. Wrote the paper: DPD AJO.

                Article
                08-PLPA-RA-1355R3
                10.1371/journal.ppat.1000389
                2663814
                19381257
                200361b2-0d7c-4611-be50-627026a3239c
                Dittmer 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
                : 4 November 2008
                : 20 March 2009
                Page count
                Pages: 14
                Categories
                Research Article
                Oncology/Hematological Malignancies
                Oncology/Sarcomas
                Oncology/Skin Cancers
                Virology/Effects of Virus Infection on Host Gene Expression
                Virology/Viruses and Cancer

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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