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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 2, Number
2, March-April 2005
| CONTENTS |
PAGE |
| Combined Oligonucleotide and Protein Microarray Temporal Analysis of p53-mediated Apoptosis. A. P. BLACK, E. WEE, T. LAMBE, A. BAILEY, L. JONES, G. S. OGG (Oxford, U.K.) |
61 |
| *A Functional Genomic Approach for Screening Preneoplastic Stages of Sporadic Colon Cancer. F. E. AHMED (Greenville, NC, U.S.A.) |
71 |
| Microarray-based Analyses of Hypoxia-induced Transcriptional Changes in Breast Cancer Cell Lines. I. HEDENFALK, N. GLARNER, A. KRONBLAD, S. VEERLA, M. RINGNER, G. LANDBERG (Lund, Sweden) |
83 |
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Microarray Data Mining for Potential Selenium Targets in Chemoprevention of Prostate Cancer.H. ZHANG, Y. DONG, H. ZHAO, J. D. BROOKS, L. HAWTHORN, N. NOWAK, J. R. MARSHALL, A. C. GAO, C. IP (Buffalo, NY; Stanford, CA, U.S.A.) |
97 |
| Molecular Determinants of Response of Tumor Cells to Berberine. T. EFFERTH, Z. CHEN, B. KAINA, GAN WANG (Heidelberg; Mainz, Germany; Guangzhou, P.R. China; Detroit, MI, U.S.A.) |
115 |
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| *Review
(page 71) |
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CANCER GENOMICS & PROTEOMICS 2: 71-84 (2005)
A Functional Genomic Approach for Screening Preneoplastic Stages of Sporadic Colon Cancer
FARID E. AHMED
Department of Radiation Oncology, Leo W. Jenkins Cancer Center,
The Brody School of Medicine (BSOM) at East Carolina University (ECU), Greenville, NC, U.S.A.
Abstract: Colon cancer is a curable disease if detected early. Microarray studies have shown that the malignant phenotype is acquired early on in colon, as in other cancers. Therefore, it becomes important to identify the molecular markers (or genes) whose expressions are implicated in early malignancy, as presented herein. Some of these genes (for example p53, Mch4 and IGFR) were shown to change their expression as they go through the various developmental stages of progression. Thus, studying the expression of these genes through the various stages of colon cancer will enhance our understanding of the mechanisms of carcinogenesis. A functional genomic approach to screen for colon cancer non invasively can be employed to test for several of these genes at the seemingly early stages of crypt foci, thereby facilitating early detection. Individuals showing aberrant expression of these genotypes can then be further screened and followed more thoroughly.
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CANCER GENOMICS & PROTEOMICS 2: 61-70 (2005)
Combined Oligonucleotide and Protein Microarray Temporal Analysis of p53-mediated Apoptosis
ANTONY P. BLACK1, EDMUND WEE1, TERESA LAMBE2, ABIGAIL BAILEY1, LOUISE JONES1, GRAHAM S. OGG1,3
1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU;
2Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford;
3Department of Dermatology, Churchill Hospital, Oxford, U.K.
Abstract: Background: P53-mediated apoptosis involves a complex process induced largely by p53 acting as a transcription factor. We hypothesised that p53 expression would lead to transcriptional events that rapidly change during apoptosis and that protein array analysis would give a more comprehensive picture of p53-mediated apoptosis than mRNA alone. Materials and Methods: We over-expressed p53 in lymphoblastoid cell lines and performed temporal analysis of functional apoptosis, assessing mRNA levels by oligo microarray and protein levels by novel antibody microarray and Western blot. Results: mRNA levels varied over time. At least 10 genes that showed enhanced expression, such as APAF-1 and GADD45, contained the p53 target sequence confirming their nature as primary p53 targets. Changes in mRNA expression did not correlate directly with changes in protein expression. Conclusion: Array analysis of protein expression in addition to mRNA expression gave a more complete assessment of p53-mediated apoptosis; for example, enhanced levels of bcl-2 and E2F2 protein were detected which, along with APAF-1, are involved in the mitochondrial apoptotic process. These data extend existing p53 array findings to correlate with protein microarray data and functional apoptosis. Furthermore they emphasize the importance of combined proteomic and genomic approaches to the investigation of p53-mediated apoptosis and other cellular processes.
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CANCER GENOMICS & PROTEOMICS 2: 83-96 (2005)
Microarray-based Analyses of Hypoxia-induced Transcriptional Changes in Breast Cancer Cell Lines
INGRID HEDENFALK1, NAOMI GLARNER1,2, ÁSA KRONBLAD1, SRINIVAS VEERLA2,3, MARKUS RINGNÅR2, GORAN LANDBERG1
1Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02, Malmo;
2Complex Systems Division, Department of Theoretical Physics, Lund University, SE-223 62, Lund;
3Department of Clinical Genetics, Lund University Hospital, SE-221 85, Lund, Sweden
Abstract: Background: Tumour hypoxia is a common characteristic of many solid human tumours, and is associated with a poor prognosis in various types of cancer. Metabolic changes occur when cells are exposed to low oxygen pressure; however, little is known about the mechanisms underlying malignant transformation and/or progression caused by hypoxia. Materials and Methods: We monitored global gene expression changes caused by hypoxia in four breast cancer cell lines using 27K cDNA microarrays. Cells were grown under hypoxic and normoxic conditions, and were harvested at four different time points. All genes were assigned to patterns (up, down, or unchanged) across the time points, followed by ontological mapping to investigate significant associations between genes belonging to specific patterns and Gene Ontology categories. Furthermore, we investigated genomic regions upstream of regulated genes for the presence of known regulatory motifs. Results: Several common effects of hypoxia were seen in the breast cancer cell lines, such as an increase in glycolytic metabolism; however, the response to hypoxia varied greatly between the cell lines. Oestrogen receptor (ER)-positive breast cancer cells displayed a partially unique response to hypoxia compared to ER-negative cells. Similarly, unique changes in e.g. RNA metabolism and DNA repair were seen in a BRCA1- deficient cell line. Whereas an enrichment of genes containing the HIF-1 binding site sequence was found among genes regulated by hypoxia in two of the cell lines investigated, this sequence was also identified in a considerable fraction of non-regulated genes. Conclusion: Global gene expression profiling of the cellular response to hypoxia revealed a multitude of novel mechanisms and functions affected by hypoxia in breast cancer cell lines. The findings also suggest a high degree of diversity in this response depending on the genetic background of the tumour cells. Specifically, down-regulation of genes involved in DNA repair mechanisms in a BRCA1-deficient cell line may reflect the crucial role played by the BRCA1 protein in instances of DNA damage, e.g. during hypoxia.
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CANCER GENOMICS & PROTEOMICS 2: 97-114 (2005)
Microarray Data Mining for Potential Selenium Targets in Chemoprevention of Prostate Cancer
HAITAO ZHANG1, YAN DONG1, HONGJUAN ZHAO2, JAMES D. BROOKS2, LESLEYANN HAWTHORN2, NORMA NOWAK3, JAMES R. MARSHALL1, ALLEN C. GAO4, CLEMENT IP1
1Division of Cancer Prevention and Population Sciences,
3Department of Cancer Genetics and
4Departments of Medicine, Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263;
2Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, U.S.A.
Abstract: Background: A previous clinical trial showed that selenium supplementation significantly reduced the incidence of prostate cancer. We report here a bioinformatics approach to gain new insights into selenium molecular targets that might be relevant to prostate cancer chemoprevention. Materials and Methods: We first performed data mining analysis to identify genes which are consistently dysregulated in prostate cancer using published datasets from gene expression profiling of clinical prostate specimens. We then devised a method to systematically analyze three selenium microarray datasets from the LNCaP human prostate cancer cells, and to match the analysis to the cohort of genes implicated in prostate carcinogenesis. Moreover, we compared the selenium datasets with two datasets obtained from expression profiling of androgen-stimulated LNCaP cells. Results: We found that selenium reverses the expression of genes implicated in prostate carcinogenesis. In addition, we found that selenium could counteract the effect of androgen on the expression of a subset obtained from androgen-regulated genes. Conclusions: The above information provides us with a treasure of new clues to investigate the mechanism of selenium chemoprevention of prostate cancer. Furthermore, these selenium target genes could also serve as biomarkers in future clinical trials to gauge the efficacy of selenium intervention.
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CANCER GENOMICS & PROTEOMICS 2: 115-124 (2005)
Molecular Determinants of Response of Tumor Cells to Berberine
THOMAS EFFERTH1, ZHONGPING CHEN2, BERND KAINA3,
GAN WANG4
1German Cancer Research Center, Heidelberg, Germany;
2Department of Neurosurgery, Cancer Center, Sun Yat-Sen University, Guangzhou, P.R. China;
3Institute of Toxicology, University of Mainz, Mainz, Germany;
4Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, U.S.A.
Abstract: Berberine, an alkaloid of Hydratis canadensis (Goldenseal), reveals profound cytotoxic activity against tumor cells. The inhibition concentration 50% (IC50) values for berberine of 60 cell lines of the National Cancer Institute (NCI) were correlated with those of 43,177 compounds included into the NCI database by COMPARE analysis. Among the standard cytostatic drugs, the IC50 values for berberine correlated significantly with those for daunorubicin, vinblastine, and paclitaxel but not with those for platinum compounds (cisplatin, carboplatin), alkylating agents (melphalan, ifosfamide), DNA topoisomerase I inhibitors (camptothecin, topothecan), and antimetabolites (5-fluorouracil, methotrexate). Significant correlations were also found to phyllanthoside, dactinomycin, didemnin B, bisantrene, maytansine, rhizoxin, geldanamycin, tetrocarcin A, and chromomycin A, most of which are involved in the multidrug resistance phenotype. Since several ATP-binding cassette (ABC) transporters confer multidrug resistance, we correlated the IC50 values for berberine with the microarray-based mRNA expression values of 31 ABC transporter genes. The expression of 8 ABC transporters correlated with the IC50 values for berberine. Using CEM/VCR1000 leukemia cells, which over-express the ABCB1 (MDR1) gene, we exemplarily validated that this ABC transporter confers resistance to berberine. Furthermore, the IC50 values for berberine of the 60 NCI cell lines were associated with microarray-based mRNA expression of 9,706 genes. By COMPARE and hierarchical cluster analyses, 20 genes were identified which significantly predicted sensitivity or resistance of the cell lines to berberine. In conclusion, the response of tumor cells to berberine is multi-factorial in nature. Novel candidate genes were identified that might determine cellular response to berberine.
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