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  • 1
    Keywords: CELLS ; EXPRESSION ; GROWTH ; DIFFERENTIATION ; PROGRESSION ; REPRESSION ; NASOPHARYNGEAL CARCINOMA ; GROUP PROTEIN EZH2 ; POLYCOMB ; GENE FUSIONS
    Abstract: Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2-ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement-independent EZH2 activation. The observed increase in differential methylation events in fusion-negative tumors can explain the tumorigenic process in the absence of genomic rearrangements. SIGNIFICANCE: In contrast to TMPRSS2-ERG -rearranged tumors, the pathomechanism for gene fusion-negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2-ERG gene fusion-negative tumors and provides a mechanistic explanation for the tumor formation process.
    Type of Publication: Journal article published
    PubMed ID: 22930729
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  • 2
    Keywords: CELLS ; GENE-EXPRESSION ; FAMILY ; GERMLINE ; SMALL RNAS ; EWINGS-SARCOMA TRANSLOCATION ; TRANSCRIPTION FACTOR ERG ; TMPRSS2-ERG FUSION ; PIWI PROTEINS ; EWS GENE
    Abstract: BACKGROUND: Overexpression of ERG transcription factor due to genomic ERG-rearrangements defines a separate molecular subtype of prostate tumors. One of the consequences of ERG accumulation is modulation of the cell's gene expression profile. Tudor domain-containing protein 1 gene (TDRD1) was reported to be differentially expressed between TMPRSS2:ERG-negative and TMPRSS2:ERG-positive prostate cancer. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of TDRD1 in ERG rearrangement-positive prostate tumors. METHODOLOGYPRINCIPAL FINDINGS: Gene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of TDRD1 and ERG (r(2) = 0.77) but not ETV1 (r(2)〈0.01) in human prostate cancer in vivo. DNA methylation analysis by MeDIP-Seq and bisulfite sequencing showed that TDRD1 expression is inversely correlated with DNA methylation at the TDRD1 promoter in vitro and in vivo (rho = -0.57). Accordingly, demethylation of the TDRD1 promoter in TMPRSS2:ERG-negative prostate cancer cells by DNA methyltransferase inhibitors resulted in TDRD1 induction. By manipulation of ERG dosage through gene silencing and forced expression we show that ERG governs loss of DNA methylation at the TDRD1 promoter-associated CpG island, leading to TDRD1 overexpression. CONCLUSIONSSIGNIFICANCE: We demonstrate that ERG is capable of disrupting a tissue-specific DNA methylation pattern at the TDRD1 promoter. As a result, TDRD1 becomes transcriptionally activated in TMPRSS2:ERG-positive prostate cancer. Given the prevalence of ERG fusions, TDRD1 overexpression is a common alteration in human prostate cancer which may be exploited for diagnostic or therapeutic procedures.
    Type of Publication: Journal article published
    PubMed ID: 23555854
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  • 3
    Keywords: CELLS ; IONIZING-RADIATION ; GENE-EXPRESSION ; CANCER-CELLS ; HEMATOPOIETIC PROGENITOR CELLS ; LENTIVIRAL VECTOR ; INTRATRACHEAL INJECTION ; antioxidant enzymes ; CONFERS RADIOPROTECTION ; DIPLOID HUMAN-LYMPHOBLASTS ; NORMAL-TISSUE
    Abstract: Gene therapy-mediated overexpression of superoxide dismutases (SOD) appears to be a promising strategy for modulating radiosensitivity based on detoxification of superoxide radicals and suppression of apoptosis. Using recombinant lentiviral-based vectors, the effects of SOD overexpression on both were tested in human lymphoblastoid cells (TK6) that are sensitive to radiation-induced apoptosis. TK6 cells were transduced with vectors containing CuZnSOD, MnSOD or inverted MnSOD (MSODi) cDNA. Gene transfer efficiency, SOD activity, superoxide-radical resistance, apoptosis and clonogenic survival were determined. A six- to eightfold increase in SOD activity was observed after transduction, rendering MnSOD-overexpressing TK6 cells significantly more resistant to paraquat-induced superoxide radical production than controls. Although significant differences in sensitivity to apoptosis were observed for MnSOD, no differences in clonogenic survival after irradiation were detected between any groups. Our data show that efficient cellular SOD overexpression, an increased superoxide radical detoxifying ability and, for MnSOD, decreased apoptosis did not result in increased clonogenic survival after irradiation. This strengthens the hypothesis of differences in the radiation-modulating effects of SOD on normal and malignant cells (protective and nonprotective, respectively), thereby showing its potential to increase the therapeutic index in future clinical SOD-based radioprotection approaches.
    Type of Publication: Journal article published
    PubMed ID: 21899432
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  • 4
    Keywords: CELLS ; ENDOTHELIAL GROWTH-FACTOR ; METASTASIS ; HUMAN COLON-CANCER ; FAMILIAL ADENOMATOUS POLYPOSIS ; FACTOR-BETA ; TGF-BETA ; CYCLOOXYGENASE-2 ; OSTEOPONTIN ; PCR DATA
    Abstract: PURPOSE: Colorectal cancer (CRC) is driven by genetic alterations causing its progression. Besides accepted tumor suppressor- and onco- genes, a series of genes have been identified, which contribute to transformation into a more malignant stage. We investigated whether the expression level of such genes, alone or in combination, could add to predict the prognosis of CRC patients. METHODS: Tumor samples from 118 CRC patients were screened in a retrospective analysis by qRT-PCR for expression of the four tumor progression-associated genes osteopontin (Opn), transforming growth factor beta (Tgf-beta), matrix metalloproteinase-2 (Mmp-2) and cyclooxigenase-2 (Cox-2). The resulting qRT-PCR values were related to those of housekeeping genes. All patients were clustered for similar expression levels between the four genes with R statistical software using the package pvclust, which provides bootstrap agglomerative hierarchical clustering. Clusters with similar expression of the four genes were analyzed for correlation with UICC stages and survival time. RESULTS: Expression of the four genes varied considerably within the cohort of patients. Cluster analysis of patients revealed a subgroup (n = 33) who in comparison with the other patients showed tenfold higher expression levels of all four genes (p 〈 0.001, respectively). However, there was no correlation between patients expressing high or low levels of these four genes and known parameters of clinical prognosis (UICC stages, survival time). CONCLUSIONS: In conclusion, tenfold increased expression levels of Opn, Tgf-beta, Mmp-2 and Cox-2 in a subset of CRC patients did not predict for a clinical outcome that is different from that of the remaining patients.
    Type of Publication: Journal article published
    PubMed ID: 22614156
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; TOXICITY ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; FORM ; ASSAY ; CELL-DEATH ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; chemotherapy ; LIPID RAFTS ; cell lines ; N-TERMINAL KINASE ; CYTOTOXICITY ; cord blood ; multiple myeloma ; ONCOLOGY ; interaction ; erufosine ; MULTIPLE-MYELOMA CELLS ; HUMAN LEUKEMIC-CELLS ; ANTICANCER ALKYLPHOSPHOLIPIDS ; Antimigratory activity ; Haematopoietic progenitors ; SELECTIVE APOPTOSIS
    Abstract: PURPOSE: Erufosine is an i.v. injectable alkylphosphocholine which is active against various haematological malignancies in vitro. In the present study, its effects on multiple myeloma (MM) cell lines and on murine and human hematopoietic progenitor cells (HPCs) were investigated. METHODS: The following MM cell lines were used: RPMI-8226, U-266 and OPM-2. The cytotoxicity of erufosine against these cell lines was determined by the MTT-dye reduction assay. Bcl-2, Bcl-X(L) and pAkt expression levels, activation of caspases, as well as cleavage of PARP, were studied by Western blotting. Migration was evaluated by a modified Boyden-chamber assay. The haematologic toxicity of erufosine was assessed using clonogenicity assays with normal HPCs of murine or human origin. RESULTS: Significant cytotoxic activity of erufosine against the MM cell lines was found. Comparison of the characteristics of erufosine-induced cell death in the three cell lines revealed a complex mode of action with apoptotic mechanisms prevailing in OPM-2 cells and non-apoptotic mechanisms prevailing in U-266 cells. The sensitivity of the MM cell lines to erufosine-induced apoptosis correlated inversely with the Bcl-X(L) expression level. Erufosine participated in synergistic interactions with various drugs. Furthermore, it showed potent migration-inhibiting activity in RPMI-8226 cells. Erufosine was not toxic to normal HPCs of murine or human origin and even stimulated progenitors from human umbilical cord blood to form granulocyte/macrophage colonies. Moreover, erufosine ameliorated the toxicity of bendamustine to murine HPCs. CONCLUSIONS: Overall, the data presented reveal that erufosine could have potential as an antimyeloma drug and deserves further development.
    Type of Publication: Journal article published
    PubMed ID: 20177898
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  • 6
    Keywords: CELLS ; GENE ; MICE ; SEQUENCES ; SITE-SPECIFIC RECOMBINATION
    Abstract: By applying the mammalian codon usage to Cre recombinase, we improved Cre expression, as determined by immunoblot and functional analysis, in three different mammalian cell lines. The improved Cre (iCre) gene was also designed to reduce the high CpG content of the prokaryotic coding sequence, thereby reducing the chances of epigenetic silencing in mammals. Transgenic iCre expressing mice were obtained with good frequency, and in these mice loxP-mediated DNA recombination was observed in all cells expressing iCre. Moreover, iCre fused to two estrogen receptor hormone binding domains for temporal control of Cre activity could also be expressed in transgenic mice. However, Cre induction after administration of tamoxifen yielded only low Cre activity. Thus, whereas efficient activation of Cre fusion proteins in the brain needs further improvements, our studies indicate that iCre should facilitate genetic experiments in the mouse.
    Type of Publication: Journal article published
    PubMed ID: 11835670
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  • 7
    Keywords: CELLS ; DISEASE ; PHOSPHORYLATION ; PH ; HYDROGEN-PEROXIDE ; REDOX STATE ; ARABIDOPSIS ; Green Fluorescent Proteins ; PERMEABILITY TRANSITION ; SUPEROXIDE FLASHES
    Abstract: Mitochondrial free radicals and redox poise are central to metabolism and cell fate. Their measurement in living cells remains a major challenge and their in vivo dynamics are poorly understood. Reports of 'superoxide flashes' in single mitochondria have therefore been perceived as a major breakthrough: single mitochondria expressing the genetically encoded sensor circularly permuted yellow fluorescent protein (cpYFP) display spontaneous flashes of fluorescence that are responsive to metabolic changes and stressors. We critically review the evidence that underpins the interpretation of mitochondrial cpYFP flashes as bursts of superoxide production and conclude that flashes do not represent superoxide bursts but instead are caused by transient alkalinisation of the mitochondrial matrix. We provide a revised framework that will help to clarify the interpretation of mitochondrial flashes.
    Type of Publication: Journal article published
    PubMed ID: 22917552
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