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      ERG Deregulation Induces PIM1 Over-Expression and Aneuploidy in Prostate Epithelial Cells

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          Abstract

          The ERG gene belongs to the ETS family of transcription factors and has been found to be involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG. We found that all three ERG fusions significantly up-regulate PIM1 expression in the NIH-3T3 cell line. PIM1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM1 induction. A significant association between ERG and PIM1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM1 expression. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.

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          Most cited references49

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          Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

          Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.
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            Delineation of prognostic biomarkers in prostate cancer.

            Prostate cancer is the most frequently diagnosed cancer in American men. Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer, but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer. Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.
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              Aneuploidy: cells losing their balance.

              A change in chromosome number that is not the exact multiple of the haploid karyotype is known as aneuploidy. This condition interferes with growth and development of an organism and is a common characteristic of solid tumors. Here, we review the history of studies on aneuploidy and summarize some of its major characteristics. We will then discuss the molecular basis for the defects caused by aneuploidy and end with speculations as to whether and how aneuploidy, despite its deleterious effects on organismal and cellular fitness, contributes to tumorigenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                30 November 2011
                : 6
                : 11
                : e28162
                Affiliations
                [1 ]Department of Clinical Medicine, University of Milano-Bicocca, Monza, Italy
                [2 ]Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
                [3 ]Unit of Molecular Genetics of Cancer, IFOM Foundation, Milano, Italy
                [4 ]Department of Pathology, S. Gerardo Hospital, Monza, Italy
                [5 ]Urology Division, Bassini ICP Hospital, Milano, Italy
                [6 ]Department of Urology, San Gerardo Hospital, Monza, Italy
                [7 ]Section of Haematology, San Gerardo Hospital, Monza, Italy
                University of Saarland Medical School, Germany
                Author notes

                Conceived and designed the experiments: VM LM CG. Performed the experiments: VM SS SR MV. Analyzed the data: VM LM RP M. Gariboldi JFR. Contributed reagents/materials/analysis tools: GB GS M. Gariboldi M. Grasso CG. Wrote the paper: VM CG. Supervised work: M. Gariboldi CG.

                [¤]

                Current address: University of Geneva, Geneva, Switzerland

                Article
                PONE-D-11-16931
                10.1371/journal.pone.0028162
                3227636
                22140532
                14ec12a0-ab6e-4ed4-942e-9681794c7e76
                Magistroni 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 August 2011
                : 2 November 2011
                Page count
                Pages: 9
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                DNA-binding proteins
                Computational Biology
                Molecular Genetics
                Gene Expression
                Genetics
                Gene Expression
                Molecular Cell Biology
                Cellular Types
                Epithelial Cells
                Gene Expression
                Medicine
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Basic Cancer Research
                Urology
                Prostate Diseases
                Prostate Cancer

                Uncategorized
                Uncategorized

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