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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 4, Number
1, January-February 2007
| CONTENTS |
PAGE |
| Transcriptomic Molecular Markers for Screening Human Colon Cancer in Stool and Tissue. F.E. AHMED, P.VOS, S. IJAMES, D.T. LYSLE, R.R. ALLISON, G. FLAKE, D.R. SINAR, W. NAZIRI, S.P. MARCUARD,R. PENNINGTON (Greenville; Chapel Hill; Triangle Park, NC; Indianapolis, IN, USA)) |
1 |
| *Telomerase: A Crucial Player in HTLV-I-induced Human T-cell Leukemia. M. BELLON, C. NICOT (KansasCity, KS, USA)) |
21 |
| Guideline for Data Analysis of Genomewide Association Studies. H. ZHANG, L. LIU, X. WANG, J.R. GRUEN (New Haven, CT, USA) |
27 |
| Low Concentrations of Beta-carotene Stimulate the Proliferation of Human Pancreatic Duct Epithelial Cells in a PKA-dependent Manner. H.A.N. AL-WADEI, M. MAJIDI, M.-S. TSAO, H.M. SCHULLER (Knoxville, TN, USA; Toronto, Ontario, Canada) |
35 |
| Molecular Mechanisms for the Antitumor Activity of Inositol Hexakisphosphate (IP6) A. BOZSIK, S. KOKENY, E. OLAH (Budapest, Hungary) |
43 |
*Review
CANCER GENOMICS & PROTEOMICS 4: 1-20 (2007)
Transcriptomic Molecular Markers for Screening Human Colon Cancer in Stool and Tissue
FARID E. AHMED1*, PAUL VOS2, STEPHANIE IJAMES3, DONALD T. LYSLE3, RON R. ALLISON1, GORDON FLAKE4, DENNIS R. SINAR5, WADE NAZIRI6, STEFAN P. MARCUARD7 and RODNEY PENNINGTON8
Departments of 1Radiation Oncology, LSB 003, Leo W. Jenkins Cancer Center and
5Internal Medicine, The Brody School of Medicine (BSOM)
at East Carolina University (ECU), Greenville, NC 27858;
2Department of Biostatistics, School of Allied Health Sciences, ECU, Greenville, NC 27858;
3Department of Psychology, University of North Carolina, Chapel Hill, NC 27599;
4Laboratory of Experimental Pathology, National Institute of Environmental
Health Sciences, Research Triangle Park, NC 27709;
6Carolina Physicians PA, Greenville, NC 27834;
7Carolina Digestive Disease, Greenville, NC 27858;
8Roche Applied Science, Indianapolis, IN 46250, U.S.A.
Abstract: There is a need for sensitive and specific diagnostic molecular markers that can be used to monitor early patterns of gene expression in non-invasive exfoliated colonocytes shed in the stool, and in situ in adenoma-carcinoma epithelium of the colon. RNA-based detection methods are more comprehensive than either DNA-, protein- or methylation-based screening methods. By routinely and systematically being able to perform quantitative gene expression studies on these samples using less than ten colon cancer genes selected by the enormous resources of the National Cancer Institute's Cancer Genome Anatomy Project, we were able to monitor changes at various stages in the neoplastic process, allowing for reliable diagnostic screening of colon cancer particularly at the early, pre-malignant stages. Although the expression of some of the genes tested in tissue showed less variability in normal or cancerous patients than in stool, the stool by itself is suitable for screening. Thus, a transcriptomic approach using stool or tissue samples promises to offer more sensitivity and specificity than currently used molecular screening methods for colon cancer. A larger prospective clinical study utilizing stool and tissue samples derived from many control and colon cancer patients, to allow for a statistically valid analysis, is now urgently required to determine the true sensitivity and specificity of the transcriptomic screening approach for this preventable cancer.
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CANCER GENOMICS & PROTEOMICS 4: 21-26 (2007)
Telomerase: A Crucial Player in HTLV-I-induced Human T-cell Leukemia
MARCIA BELLON, CHRISTOPHE NICOT
University of Kansas Medical Center, Department of Microbiology, Immunology and Molecular Genetics,
3025 Wahl Hall West, 3901 Rainbow Blvd, Kansas City, KS 66160, U.S.A.
Abstract: One in seven types of human cancer is associated with an oncogenic virus infection. Most human tumors have high telomerase activity but very short telomeres, yet the maintenance of these short telomeres is critical to avoid telomere end fusion or senescence and to support active proliferation. Oncogenic viruses have evolved a wide repertoire of strategies to stimulate telomerase functions at the transcriptional and post-transcriptional levels. Since telomerase activity is absent in somatic cells, the inhibition of telomerase is an attractive target for cancer therapeutics.
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CANCER GENOMICS & PROTEOMICS 4: 27-34 (2007)
Guideline for Data Analysis of Genomewide Association Studies
HEPING ZHANG, LEI LIU, XUEQIN WANG, JEFFREY R. GRUEN
Yale University School of Medicine, New Haven, CT, U.S.A.
Abstract: Intensive efforts have been underway to identify common genetic factors that influence health and disease including cancer using genomewide association studies (GWAS). Our experiences have shown that while it is more advantageous to have large detailed data sets, the amount of information generated by GWAS also present major challenges for statistical analyses. While prospects for the oncoming flood of GWAS is exciting, the tools for conducting and evaluating these studies are still in early developmental stages creating some investigator uncertainty and prompting conferences and workshops specifically devoted to these topics. In this review, we summarize important steps for planning the statistical analysis involving genome-wide data from single nucleotide polymorphisms (SNPs). This review is purposely meant to be relatively short and of practical use for the space constraints of typical federal grant proposals.
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CANCER GENOMICS & PROTEOMICS 4: 43-52 (2007)
Molecular Mechanisms for the Antitumor Activity of Inositol Hexakisphosphate (IP6)
ANIKO BOZSIK, SZABOLCS KOKENY, EDITH OLAH
National Institute of Oncology, Department of Molecular Genetics,
Budapest, H-1122, Hungary
Abstract: Background: Inositol hexakisphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has been reported to have significant in vivo and in vitro anticancer activity against numerous tumors. However, the molecular mechanism of the anticancer effect of IP6 has not been fully elucidated. Materials and Methods: Using K-562 human leukemia cells we analysed the induction of the erythroid differentiation program, as well as modulation of the gene expression profile of K-562 leukemia cells treated with IP6. Results: A single treatment with IP6 (0.75 or 5.0 mM) resulted in a time- and dose-dependent growth inhibition of K-562 cells and also activation of the erythroid differentiation program. K-562 cells expressed a concomitant differentiation after 12 hours of exposure. Possible molecular mechanisms and key signaling pathways, as well as gene expression behind this anticancer effect were examined using oligonucleotide microarrays and quantitative real-time PCR. Treatment with IP6 (750 IM, 5 mM) had a marked impact, resulting in early (60 min) and late (12 h) modulation of expression of about 1800 and 1200 transcripts (at p<0.05). Through microarray analysis, the anticancer effect of IP6 in K-562 was found to be associated with the modulation of multiple genes involved in immunity, Wnt and IGF pathways, PI3 kinase signaling and apoptosis. Using selected subsets of genes, the microarray hits could be validated by Q-PCR. A 2-fold upregulation of the apoptosis pathway, measured using the BAX/BCL-2 ratio was observed for 12 hours. IP6 (5 mM) induced up to 6-fold increases in differentiation measured by hemoglobin synthesis, yielding up to 70% of benzidine-positive cells at 120 hours. Conclusion: The results of this study show that IP6 is a strong inducer of differentiation (cytostatic effect) and a moderately strong inducer of apoptosis (cytotoxic effect). Evidence has been provided to show that the growth inhibitory effects of IP6 are mediated through the modulation of key signaling pathways.
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CANCER GENOMICS & PROTEOMICS 4: 35-42 (2007)
Low Concentrations of Beta-carotene Stimulate the Proliferation of Human Pancreatic Duct Epithelial Cells in a PKA-dependent Manner
HUSSEIN A. N. AL-WADEI1, MOURAD MAJIDI1, MING-SOUND TSAO2, HILDEGARD M. SCHULLER1
1Experimental Oncology Laboratory, Department of Pathobiology,
College of Veterinary Medicine, University of Tennessee, Knoxville, TN, U.S.A.;
2Division of Cellular and Molecular Biology, Department of Pathology, Ontario
Cancer Institute/Princess Margaret Hospital, University of Toronto,
Toronto, Ontario, Canada.
Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most common causes of cancer death. Preclinical and clinical studies on the preventive effects of beta-carotene or other retinoids have used dietary supplements that yielded high systemic concentrations (1-50 µM). While some of the preclinical data suggested cancer preventive effects of these agents, they have disappointed in clinical investigations. Materials and Methods: The effects of low concentrations (10 fM-200 nM)of beta-carotene on the proliferation, intracellular cAMP levels, PKA activation status and phosphorylation of EGFR-specific tyrosine kinases and ERK1/2 in immortalized human pancreatic duct epithelial cells was investigated. Results: Our data show significant concentration-dependent and PKA-dependent stimulation of all measured endpoints. Similar responses were achieved with forskolin. Our data indicate that low concentrations of beta-carotene stimulate the proliferation of the putative origin of PDAC, pancreatic duct epithelial cells via cAMP and PKA-dependent transactivation of the EGFR pathway. This could potentially have promoting effects on the development of PDAC.
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