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      MiR-92b and miR-9/9* Are Specifically Expressed in Brain Primary Tumors and Can Be Used to Differentiate Primary from Metastatic Brain Tumors

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          Abstract

          A recurring challenge for brain pathologists is to diagnose whether a brain malignancy is a primary tumor or a metastasis from some other tissue. The accurate diagnosis of brain malignancies is essential for selection of proper treatment. MicroRNAs are a class of small non-coding RNA species that regulate gene expression; many exhibit tissue-specific expression and are misregulated in cancer. Using microRNA expression profiling, we found that hsa-miR-92b and hsa-miR-9/hsa-miR-9* are over-expressed, specifically in brain primary tumors, as compared to primary tumors from other tissues and their metastases to the brain. By considering the expression of only these two microRNAs, it is possible to distinguish between primary and metastatic brain tumors with very high accuracy. These microRNAs thus represent excellent biomarkers for brain primary tumors. Previous reports have found that hsa-miR-92b and hsa-miR-9/hsa-miR-9* are expressed more strongly in developing neurons and brain than in adult brain. Thus, their specific over-expression in brain primary tumors supports a functional role for these microRNAs or a link between neuronal stem cells and brain tumorigenesis.

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          Most cited references28

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          Transcriptional activation of miR-34a contributes to p53-mediated apoptosis.

          p53 is a potent tumor suppressor, whose biological effects are largely due to its function as a transcriptional regulator. Here we report that, in addition to regulating the expression of hundreds of protein-coding genes, p53 also modulates the levels of microRNAs (miRNAs). Specifically, p53 can induce expression of microRNA-34a (miR-34a) in cultured cells as well as in irradiated mice, by binding to a perfect p53 binding site located within the gene that gives rise to miR-34a. Processing of the primary transcript into mature miR-34a involves the excision of a 30 kb intron. Notably, inactivation of miR-34a strongly attenuates p53-mediated apoptosis in cells exposed to genotoxic stress, whereas overexpression of miR-34a mildly increases apoptosis. Hence, miR-34a is a direct proapoptotic transcriptional target of p53 that can mediate some of p53's biological effects. Perturbation of miR-34a expression, as occurs in some human cancers, may thus contribute to tumorigenesis by attenuating p53-dependent apoptosis.
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            DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal.

            The molecular controls that govern the differentiation of embryonic stem (ES) cells remain poorly understood. DGCR8 is an RNA-binding protein that assists the RNase III enzyme Drosha in the processing of microRNAs (miRNAs), a subclass of small RNAs. Here we study the role of miRNAs in ES cell differentiation by generating a Dgcr8 knockout model. Analysis of mouse knockout ES cells shows that DGCR8 is essential for biogenesis of miRNAs. On the induction of differentiation, DGCR8-deficient ES cells do not fully downregulate pluripotency markers and retain the ability to produce ES cell colonies; however, they do express some markers of differentiation. This phenotype differs from that reported for Dicer1 knockout cells, suggesting that Dicer has miRNA-independent roles in ES cell function. Our findings indicate that miRNAs function in the silencing of ES cell self-renewal that normally occurs with the induction of differentiation.
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              MicroRNAs accurately identify cancer tissue origin.

              MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.
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                Author and article information

                Journal
                Brain Pathol
                bpa
                Brain Pathology (Zurich, Switzerland)
                Blackwell Publishing Ltd
                1015-6305
                1750-3639
                July 2009
                : 19
                : 3
                : 375-383
                Affiliations
                [1 ]simpleDepartmentof Pathology, Sheba Medical Center Tel-Hashomer, Israel
                [2 ]simpleSackler School of Medicine, Tel-Aviv University Tel-Aviv, Israel
                [3 ]simpleRosetta Genomics Ltd. Rehovot, Israel
                [4 ]simpleSoroka University Medical Center Beer-Sheva, Israel
                [5 ]simpleDepartment of Pathology, Beilinson hospital, Rabin Medical Center Petah-Tikva, Israel
                [6 ]simplePathology Institute, Sourasky Medical Center Tel Aviv, Israel
                Author notes
                Corresponding author: Nitzan Rosenfeld, Ph.D., Rosetta Genomics Ltd., 10 Plaut St., Rehovot, 76706 Israel (E-mail: nitzan@ 123456rosettagenomics.com )
                [*]

                These authors contributed equally to this work.

                [**]

                These two principal investigators equally supervised the work.

                Article
                10.1111/j.1750-3639.2008.00184.x
                2728890
                18624795
                c0faf5b3-7f0d-4b26-ae34-d3dc80431c6b
                Journal compilation © 2009 International Society of Neuropathology

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 11 December 2007
                : 29 April 2008
                : 30 April 2008
                Categories
                Research Articles

                Pathology
                microrna expression,tumor classification,molecular diagnostics
                Pathology
                microrna expression, tumor classification, molecular diagnostics

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