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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 1, Number
5-6, September-December 2004
| CONTENTS |
PAGE |
| Altered IL-12 Signaling Pathways Contribute to the Deficient IFN-A Production by T Splenocytes from Tumor-bearing Mice. M. TORROELLA-KOURI, L. M. HERBERT, G. PERRY, D. M. LOPEZ (Miami, FL, U.S.A.) |
345 |
| The Melanoma Vascular Mimicry Phenotype Defined in Gene Expression and Microsome Sequencing Analysis. J. JU, L. RASTELLI, U. M. MALYANKER, J. F. SIMONS, C. HUANG, J. HERRMANN, J. R. MACDOUGALL, B. TAILLON (Mobile, AL; New Haven, CT, U.S.A.) |
355 |
| Microarray-based Prediction of Cytotoxicity of Tumor Cells to Arsenic Trioxide. T. EFFERTH, B. KAINA (Heidelberg; Mainz, Germany) |
363 |
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A New Microarray, Enriched in Pancreas and Pancreatic Cancer cDNAs to Identify Genes Relevant to Pancreatic Cancer. K. L. POGUE-GEILE, J. A. MACKEY, R. D. GEORGE, P. G. WOOD, K. K.W. LEE, A. J. MOSER, D. L. TILLMAN, J. LYONS-WEILER, D. C. WHITCOMB (Pittsburgh, PA, U.S.A.) |
371 |
| Epigenetic Up-regulation of Gene Expression in KAS 6/1 Human Multiple Myeloma Cells. C. POMPEIA, D. R. HODGE, B. PENG, C. PLASS, Y.-Z. WU, W. L. FARRAR (Maryland; Ohio, U.S.A.) |
387 |
| In Vivo and In Vitro Analysis of IL-10 in the NZB Leukemic Model. B. A. McCARTHY, S. Y. CHONG, G. PARKER, M. MERAMO, M. ZHANG, J. CZARNESKI, A. MANSOUR, E. RAVECHE (Newark, NJ; Boston, MA, U.S.A.) |
407 |
| Analysis of the p53-hMDM2-p21 (WAF1/CIP1) Cell Cycle Regulation Pathway in Malignant Fibrous Histiocytomas. U. BRINCK, T. SCHLOTT, C. CORDON-CARDO, J. STACHURA, M. WALZ, G. FISCHER, M. KORABIOWSKA (Gottingen, Uelzen, Germany; New York, U.S.A.; Krakow, Poland) |
419 |
| Proteomic Profiling of Signaling Proteins in Ten Different Tumor Cell Lines. L. AFJEHI-SADAT, E. ENGIDAWORK, M. FELIZARDO-CABATIC, I. SLAVC, G. LUBEC (Vienna, Austria; Addis Ababa, Ethiopia) |
427 |
| Effects of Tumor Necrosis Factor-· (TNF·) and Interferon-A (IFNA) on Gene Expression Profiles in Bladder Carcinoma Cells Using Oligonucleotide Microarray Analysis.
P. CHAMPELOVIER, M. EL ATIFI, F. MANTEL, S. MICHALLAT, A. SIMON, B. ROSTAING, F. BERGER, D. SEIGNEURIN (Grenoble, France) |
455 |
| Volume 1, 2004, Index |
467 |
CANCER GENOMICS & PROTEOMICS 1: 419-426 (2004)
Analysis of the p53-hMDM2-p21 (WAF1/CIP1) Cell Cycle Regulation Pathway in Malignant Fibrous Histiocytomas
ULRICH BRINCK1, THILO SCHLOTT2, CARLOS CORDON-CARDO3, JERZY STACHURA4, MARTIN WALZ5, GOSTA FISCHER1, MONIKA KORABIOWSKA1
1Department of Pathology, Reinhard Nieter Hospital, Friedrich Paffrath Str. 100, 26389 Wilhelmshaven, Academic Hospital of the University Gottingen, Gottingen;
2Department of Pathology, University Gottingen, Robert Koch Str. 40, 37075 Gottingen, Germany;
3Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, 1075 York Avenue, 10021 New York, U.S.A.;
4Department of Pathology, Jagiellonian University, Grzegorzecka 16, 30531 Krakow, Poland;
5Department of Traumatic and Reconstructive Surgery, Kliniken Uelzen & Bad Bevensen, Hagenskamp 34, 29525 Uelzen, Germany
Abstract: This study was undertaken to analyze patterns of expression of critical cell cycle regulators (CCR) involved in the p53 pathway in malignant fibrous histiocytomas (MFH). Protein expression was assessed using immunohistochemistry analyzing p53, hMDM2 and p21 (WAF1/CIP1) phenotypes. p53- and hMDM2-positive phenotypes were found to be associated with low p21 levels (p<0.01). Positive hMDM2 phenotype did not correlate with any hMDM2 mutations, which in our tumor collective were not found. High-grade MFH differed from MFH grade I and II concerning higher p53 and lower p21 levels, while hMDM2 expression was independent of grade. Inclusion of categorized values into a Cox regression study proved the independent prognostic relevance of p53, hMDM2 and p21 phenotypes.
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CANCER GENOMICS & PROTEOMICS 1: 355-362 (2004)
The Melanoma Vascular Mimicry Phenotype Defined in Gene Expression and Microsome Sequencing Analysis
JINGFANG JU1, LUCA RASTELLI2, URIEL M. MALYANKER2, JAN F. SIMONS2,
CHUNLI HUANG2, JOHN HERRMANN2, JOHN R. MACDOUGALL2, BRUCE E. TAILLON2
1USA-Cancer Research Institute, Mobile, AL; 2CuraGen Corporation Inc.
New Haven, CT, U.S.A.
Abstract: The phenomenon of vasculogenic mimicry in melanoma has been recently described to be an important factor relating to melanoma progression. Large scale gene expression profiling by real-time quantitative RT-QPCR of a panel of 40 normal tissues and 54 cancer cell lines revealed that two genetically related melanoma cell lines, one derived from a primary lesion Hs.688(A) and one derived from a lymph node metastasis Hs.688(B), displayed a unique expression pattern when compared to other cancer cell lines and tissue samples in the panel. Quantitative-RT-PCR data indicated that these melanoma cells expressed a number of activated endothelial cell-associated genes such as tissue inhibitors of matrix metalloproteinases TIMP-2, matrix metalloproteinase (MMP-1, MMP-2), thrombospondin 1 (TSP1), proto-oncogene c-MET and vascular endothelial growth factor (VEGF). To examine the gene expression profile of these unique melanoma cells in greater depth, cDNA libraries were made from isolated microsome complexes to enrich those transcripts that were destined to be translated into cell surface or secreted proteins. High throughput sequencing analysis revealed that this library contained over 7000 cDNAs and was enriched by over 80% of secreted or membrane-bound proteins. The presence in the cDNA library of genes such as acetyl LDL receptor, tumor endothelial markers-1, 5 and 8 (TEMs), flow-induced endothelial G protein coupled receptor-1 and VEGF-related protein (VRP), all of which are known to be expressed uniquely by endothelial cells, supported the hypothesis that Hs.688(A) and Hs.688(B) cells were mimicking an activated vascular phenotype. Ultimately the goal is to investigate the biological roles of endothelial cell-associated genes in the behavior of Hs.688(A) and Hs.688 (B) melanoma cells.
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CANCER GENOMICS & PROTEOMICS 1: 371-386 (2004)
A New Microarray, Enriched in Pancreas and Pancreatic Cancer cDNAs to Identify Genes Relevant to Pancreatic Cancer
KAY L. POGUE-GEILE1, JULIE A. MACKEY1, RYAN D. GEORGE1, PAUL G. WOOD2, KENNETH K.W. LEE3, A. JAMES MOSER3, DERRICK L. TILLMAN4, JAMES LYONS-WEILER4, DAVID C. WHITCOMB 1,5
1Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, 5117 Centre Ave, 2.32E Hillman Cancer Center, Pittsburgh, PA 15213;
2Center of Human Genetics and Integrative Biology, W944 Biomedical Science Tower North, 200 Lothrop St, Pittsburgh, PA, 15213;
3Department of Surgery, 497 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261;
4Center for Pathology and Oncology Informatics, University of Pittsburgh Medical Center Cancer Pavilion, Suite 301, 5230 Centre Ave, Pittsburgh, PA 15232;
5Departments of Cell Biology and Physiology and Human Genetics and the University of Pittsburgh Cancer Institute, 200 Lothroop St, M2C Wing UPMC Presbyterian, Pittsburgh, PA 15213, U.S.A.
Abstract: Background: Identification and characterization of genes that are relevant to pancreatic cancer remains a priority for developing detection and diagnostic tests and identifying targets for treatment. Materials and Methods: In order to discover relevant genes, we developed a microarray composed of 5763 pancreas and pancreatic cancer cDNA clones, representing genes of known and unknown function. The Pittsburgh Pancreas Enriched ARray (PittPEAR) was used to compare the gene expression differences between pancreatic cancer and normal pancreas. Results: Two hundred and sixty-four genes were identified: 85 were overexpressed and 176 were underexpressed in cancer compared to normal tissue. Two of the top five genes included the cell cycle division 37 (CDC37) and period Drosophila homolog protein 1 (PER1), which play critical roles in cell division and transcriptional regulation, respectively. Underexpression of many genes probably reflected the loss of acinar and islet cells from the tumors. The biological functions of overexpressed genes include immune response genes, cytoskeletal and genes related to the extracellular matrix, cell invasion, migration, adhesion and motility. Apoptosis and transcription factor genes were also identified. Conclusion: We conclude that the PittPEAR microarray provides a useful tool for identifying genes that are relevant to the development and maintenance of pancreatic cancer.
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CANCER GENOMICS & PROTEOMICS 1: 387-406 (2004)
Epigenetic Up-regulation of Gene Expression in KAS 6/1 Human Multiple Myeloma Cells
CELINE POMPEIA1, DAVID R. HODGE1, BENJAMIN PENG1, CHRISTOPH PLASS2, YUE-ZHONG WU2, WILLIAM L. FARRAR1
1Laboratory of Molecular Immunoregulation, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702;
2Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, U.S.A.
Abstract: Cytosine methylation, an epigenetic form of regulating gene transcription, has gained importance upon the discovery that genes involved in the carcinogenic process may be regulated by this mechanism and, moreover, that certain cancers respond to treatment with demethylation-promoting drugs. Typically, the use of DNA methyltransferase inhibitor drugs results in the up-regulation of important tumor suppressor genes, previously down-regulated by the existence of abnormal cytosine methylation within their promoters. Here, we show microarray and RT-PCR results indicating that many genes are down-regulated upon treatment of KAS 6/1 multiple myeloma cells with Zebularine, a demethylating agent. Our findings suggest that, in addition to the typical methylation inhibitor-induced up-regulation of genes, removal of methylation in some genes may have a profound down-regulating effect upon their expression. The analysis of gene function showed that, of the down-regulated genes, 38 are associated with cell proliferation and/or cancer. Our analysis of the promoters of the subset of selected genes containing CpG islands showed that the distribution of cis elements differs between genes up- and down-regulated by methylation. Finally, we propose a model which shows how genes containing methylation sites within their basic promoters and/or enhancer sequences are susceptible to down-regulation, whereas genes methylated within silencer regions are up-regulated, thus providing a model as to how DNA methylation could induce such opposing effects on transcription.
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CANCER GENOMICS & PROTEOMICS 1: 455-464 (2004)
Effects of Tumor Necrosis Factor-á(TNFa) and Interferon-ã (IFNã) on Gene Expression Profiles in Bladder Carcinoma Cells Using Oligonucleotide Microarray Analysis
PIERRE CHAMPELOVIER1, MICHELE EL ATIFI2, FREDERIC MANTEL2, SANDRINE MICHALLAT2, ANNICK SIMON3, BEATRICE ROSTAING2, FRANCOIS BERGER2,
DANIEL SEIGNEURIN1
1Laboratoire de Cytologie, Departement d¢Anatomie et de Cytologie Pathologique and 3Laboratoire d¢Hématologie, Département de Biologie et de Pathologie de la Cellule, Centre Hospitalier Universitaire de Grenoble, Hopital Albert Michallon, BP 217, 38043, Grenoble cedex;
2Equipe Transcriptome, INSERM U318, Laboratoire de Neurosciences Precliniques, Universite Joseph Fourier, 38000, Grenoble, France
Abstract: Background: TNFá and IFNã, two main cytokines secreted in the urine of bladder cancer patients after Bacillus Calmette Guerin immunotherapy (BCG therapy), exert various responses ranging from growth arrest, apoptosis, phenotypic changes and differentiation. Materials and Methods: To identify their transcriptional and translational targets, the highly sensitive bladder cancer cell line (RT112) was treated for 24 hours with increasing doses of IFNã or TNFá and analyzed for cellular and molecular changes using a cDNA microarray technique (Transcriptome) containing 800 genes. Results: High doses (>10 ng/ml) induced an apoptotic cell death, whereas low doses (<5 ng/ml) induced a survival program. TNFá-inducible genes, IFNã-inducible genes and genes modulated by TNFá and IFNã together were identified. All were related to the tumor progression program including cell proliferation, apoptosis/survival, angiogenesis and metastatic processes. Conclusion: These results suggest that the transcriptomic approach could be a good methodology to determine the molecular mechanisms involved in bladder tumor progression processes in relation to a low response to BCG treatment. However, mRNA and protein expression did not always correlate, suggesting that translational regulation is a vital process in bladder tumor progression.
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CANCER GENOMICS & PROTEOMICS 1: 363-370 (2004)
Microarray-based Prediction of Cytotoxicity of Tumor Cells to Arsenic Trioxide
THOMAS EFFERTH1, BERND KAINA2
1Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg;
2Institute of Toxicology, University of Mainz, Mainz, Germany
Abstract: Arsenic has been used since ancient times as a medicinal agent. Currently, arsenic trioxide is experiencing a thriving revival in modern oncology. The aim of this study was to identify the molecular predictors of sensitivity and resistance to arsenic trioxide. We mined the microarray database of the National Cancer Institute (NCI), USA, for genes whose expression correlated with the IC50 values for arsenic trioxide of 60 cell lines of different tumor types. By COMPARE analysis, Kendall's ô test, and false discovery rate (FDR) analyses, 47 out of 9706 genes or expressed sequence tags (ESTs) were identified. If the mRNA expression of the 47 genes or ESTs was subjected to hierarchical cluster analysis and cluster image mapping, sensitivity or resistance of the 60 cell lines to arsenic trioxide was predictable with statistical significance (p=1.01 x 10-5). While the proteins encoded by the 47 genes identified differ in their specific functions (signal transducers, transcription factors, proteasome degradation proteins, proliferation-related proteins, regulators of oxidative stress etc.), it is intriguing that many of them are in one way or another involved in the apoptotic machinery, indicating that apoptosis is an important mechanism of arsenic trioxide's cytotoxicity.
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CANCER GENOMICS & PROTEOMICS 1: 345-354 (2004)
Altered IL-12 Signaling Pathways Contribute to the Deficient IFN-ã Production by T Splenocytes from Tumor-bearing Mice
MARTA TORROELLA-KOURI, LYNN M. HERBERT, GISELLE PERRY, DIANA M. LOPEZ
Department of Microbiology and Immunology, University of Miami School of Medicine and the Sylvester Comprehensive Cancer Center, Miami, FL 33136, U.S.A.
Abstract: IFN-ã is a crucial cytokine produced by T and NK cells. Previous work from our laboratory has reported that in T cells of BALB/c mice bearing the D1-DMBA-3 mammary tumor, IFN-ã production is down-regulated, due to decreased expression of IL-12 by macrophages of tumor bearers. IL-12 is the main inducer of IFN-ã production in T and NK cells. To exert its function, IL-12 interacts with its receptor (IL-12R), activating a JAK/STAT signaling pathway. Our investigation suggests that there is also a deficiency in the response to IL-12 by T cells from tumor hosts. The present work reports the results of RT-PCR experiments in the study of the IL-12R expression on T cells from normal and tumor bearers. Data showed a deficient expression of the IL-12Râ2 chain on T cells from tumor hosts. Gene expression arrays on IL-12-activated T cells from normal and tumor bearers confirmed the RT-PCR results, and also showed decreased expression of IL-18Rá in tumor bearers' T cells. Arrays also showed down-regulated expression of JAK2, STAT 1, 3, 4 and IRF-1. Finally, increased expression of SOCS 1,3,4,5 and 7, as well of Protein inhibitor of activated STATs (Pias) 1 and y was also observed in tumor bearers' T cells.
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CANCER GENOMICS & PROTEOMICS 1: 427-454 (2004)
Proteomic Profiling of Signaling Proteins in Ten Different Tumor Cell Lines
LEILA AFJEHI-SADAT1, EPHREM ENGIDAWORK1,2, MAUREEN FELIZARDO-CABATIC1,
IRENE SLAVC1, GERT LUBEC1
1Department of Pediatrcs, Division of Basic Sciences, Medical University of Vienna, Vienna, Austria;
2Department of Pharmacology, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia
Abstract: Normal cell development requires a coordinated and organised reaction and adaptation to the constantly changing environment. Cells achieve this by a network of signaling pathways comprising proteins that serve as molecular switches. Subversion of these intracellular signaling pathways is implicated in several diseases, including cancer. To better understand the mechanisms of this process and to identify potential biomarkers and/or therapeutic targets at the protein level, we performed two-dimensional electrophoresis (2-DE) and mass spectrometry in ten different tumor cell lines. Following separation by high resolution 2-DE, a series of seventy signaling proteins were unambiguously identified that were differentially expressed in different cell lines. Signaling proteins of immense significance in cancer biology including two proteins of the 14-3-3 protein family, growth factor receptor bound protein 2, Cdc25B phosphatase, disheveled associated activator of morphogenesis-1, putative ORF1, zyxin, phosphatidylethanolamine-binding protein, Rho/Rab GDP-dissociation inhibitors, Stam binding protein, SH3 domain GRB2-like protein B2, Cullin homolog 3, Coronin-1B, calcium binding proteins and enzymes with signaling function displayed tumor cell line-specific expression. Other signaling proteins of importance, such as maspin, nucleoside diphosphate kinase-A, Ser/Thr kinases, Ser/Thr phosphatases, septins, annexins and receptor for hyaluronic acid-mediated motility, however, showed tumor cell line-associated expression. These data highlight that there might be specific and shared signaling pathways that are activated in the chain of events leading to tumor formation. Moreover, the data open up the possibility of developing new prognostic markers, as well as widening the avenue of cancer chemotherapy.
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CANCER GENOMICS & PROTEOMICS 1: 407-418 (2004)
In Vivo and In Vitro Analysis of IL-10 in the NZB Leukemic Model
BRIAN A. McCARTHY1, SIEW YEN CHONG1, GEORGE PARKER1, MONIQUE MERAMO1, MING ZHANG2, JENNIFER CZARNESKI1, AMAL MANSOUR1, ELIZABETH RAVECHE1
1New Jersey Medical School/UMDNJ, Newark, NJ; 2Harvard Medical School, Boston, MA, U.S.A.
Abstract: Background: The B-1 malignancy, CLL has been associated with a failure to undergo apoptosis and increased endogenous IL-10 production. This study was undertaken to identify IL-10 effects in the NZB murine model of CLL. Materials and Methods: Antisense IL-10 was employed in vitro and in vivo to decrease IL-10 protein. Following treatment, cells were analyzed for alterations in cell cycle and RNA was studied for alterations in gene expression. Additional in vivo studies employed NZB mice in which the IL-10 gene was deleted. Results: IL-10 (-/-) knockout NZB mice overwhelmingly failed to develop leukemia. In vitro antisense IL-10 treatment resulted in a G2/M block and apoptosis and in vivo treatment with antisense IL-10 increased the survival of mice. Microarray analysis indicated a significant role for IL-10 in cell cycle regulation via cdc25C up-regulation and decreased p47phox redox activity. Conclusion: In summary, IL-10 is a critical survival factor for malignant B cells via anti-apoptotic and cell cycle effects.
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