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Untitled Document
CANCER GENOMICS & PROTEOMICS
Volume 1, Number
1, January-February 2004
| CONTENTS |
PAGE |
| Establishment
and Validation of Quantitative Real-time PCR Assay for Aberrant Methylation of 14-3-3ó Gene in Breast and Lung Carcinoma*. U. G. SATHYANARAYANA,
M. SUZUKI, S. TOYOOKA, A. PADAR, K. O. TOYOOKA, A. L.
ZERN, K. MIYAJIMA, T. TAKAHASHI, E. BRAMBILLA. A. F. GAZDAR. (Dallas, TX, U.S.A.;Nagoya, Japan; Grenoble, France) |
1 |
| Detection
of Chromosomal Aberrations in Transitional Cell Carcinoma of the Bladder by Representational Difference Analysis. O. MOUSSA, G. SZALAI,
H. ABOL-ENEIN, N. K. BISSADA, M. A. GHONEIM, D. K. WATSON (Charleston, SC; Little Rock, AR, U.S.A.; Mansoura, Egypt) |
9 |
| Protein Expression
Profiles Indicative for Drug Resistance of Kidney Carcinoma. T. EFFERTH, M. VOLM (Heidelberg, Germany) |
17 |
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Molecular
Profiling of Circulating Cytokine Levels in Human Ovarian Cancer Patients. R. HUANG, Y. LIN, L. FLOWERS, H. LISOUKOV, Q. WANG, Q.SHI, I. R. HOROWITZ, S. PARTHASARATHY, R-P. HUANG (Atlanta, GA; Boston, MA, U.S.A) |
23 |
| SMAD4-related Familial Juvenile Polyposis Syndrome with Colon Cancer. P. MOGUELET, L.-F. PLASSA, J. METAYER, P. TENIERE, S. OLSCHWANG, T. FREBOURG, M. LEGRAND, H. DE THE, A. JANIN, P. BERTHEAU (Paris; Rouen, France) |
33 |
| The X-chromosome RBMX Gene is Expressed in Mammary Carcinoma. F. GOMEZ-ESQUER, D. AGUDO, F. MARTINEZ-ARRIBAS, M.J. NUNEZ-VILLAR, M. POLLAN, J. SCHNEIDER (Madrid, Spain) |
39 |
| Application of Newly Developed Tissue-arrays to Study EMMPRIN (CD147) Expression in Malignant Non-Hodgkin Lymphoma. C. THORNS, F. NOACK, A. C. FELLER, H. MERZ, W. STOCKER, E. MUELLER-KUNERT, H.-W. BERND (Luebeck, Germany) |
45 |
| Altered Levels
of Cytochrome P450 Genes in Hepatitis B orC Virus-infected Liver Identified by Oligonucleotide Microarray. N. IIZUKA,
M. OKA, Y. HAMAMOTO, N. MORI, T. TAMESA, A. TANGOKU, T. MIYAMOTO, S. UCHIMURA, H. NAKAYAMA, K. HAMADA, H. YAMADA-OKABE (Yamaguchi; Kanagawa, Japan) |
53 |
| *Atomic Force Microscopy as a Tool in Nanobiology Part I: Imaging and Manipulation in Cytogenetics.
S. THALHAMMER, W. M. HECKL (Munich, Germany) |
59 |
| *Atomic Force Microscopy as a Tool in Nanobiology Part II: Force Spectroscopy in Genomics and Proteomics. L. T. COSTA, S. THALHAMMER W. M. HECKL (Munich, Germany) |
71 |
| Cadmium Induces Fas Down-Regulation in a Human Immature T-cell Line. G. TH. TSANGARIS, A. BOTSONIS, I. POLITIS, F. TZORTZATOU STATHOPOULOU (Athens, Greece) |
77 |
| Correlation Between Interferon Alpha Receptor Protein Expression and Sensitivity to Interferon Alpha Subtypes in Human Renal Carcinoma Cell Lines. T. ARIYASU, N. FUJIOKA, S. YAMAMOTO, Y. YANAI, H. YAMAUCHI, H. IKEGAMI, M. IKEDA, M. KURIMOTO, S. HORIE, T. KITAMURA (Okayama; Tokyo, Japan) |
87 |
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| *Reviews
(pp 59,71) |
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CANCER GENOMICS & PROTEOMICS 1: 77-86 (2004)
Cadmium Induces Fas Down-Regulation in a Human Immature T-cell Line
GEORGE TH. TSANGARIS1,2, ATHANASIOS BOTSONIS2, IOANNIS POLITIS2, FOTINI TZORTZATOU-STATHOPOULOU2
1University Research Institute for the Study and Treatment of Childhood Genetic and Malignant Diseases and 2Oncology Unit, First Department of Paediatrics, University of Athens, "Aghia Sophia" Childrens' Hospital, Athens, Greece
Abstract: Cadmium (Cd2+) is an ubiquitous toxic metal with apoptotic and genotoxic effects, which has been involved in a variety of pathological conditions inducing disturbance of the immune system. In the present study we treated the Fas-expressed human immature T-cell line CCRF-CEM with 10ìM Cd2+ for 6h or 24h. We found that pretreatment of the cells with Cd2+ for 24h inhibited apoptosis induced by Fas-ligation with the CH-11 antibody, in contrast to pretreatment for 6h. Immunocytochemical and multiplex RT-PCR analyses indicated that Cd2+ treatment for 24h inhibited Fas expression at the transcriptional level. To investigate that effect of Cd2+, cDNA microarray analysis was applied, which indicated that the rapid induction of NF-kB, ERK5 and JAK3 genes by Cd2+ was the initial step resulting in Fas down-regulation. The Fas down-regulation induced by Cd2+ seems to be responsible for the carcinogenic and the immunomodulatory effects of that metal.
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CANCER GENOMICS & PROTEOMICS 1: 23-32 (2004)
Molecular Profiling of Circulating Cytokine Levels in Human Ovarian Cancer Patients
RUOCHUN HUANG1, YING LIN1, LISA FLOWERS1, HENRY LISOUKOV2, QIAN WANG2, QIAN SHI1, IRA R. HOROWITZ1, SAMPATH PARTHASARATHY1, RUO-PAN HUANG1
1Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322;
2PerkinElmer Life and Analytical Sciences, 549 Albany St, Boston, MA 02118, U.S.A.
Abstract: Background: Growing evidence suggests that cytokines not only are associated with ovarian cancer development, drug resistance and metastasis, but also may provide valuable markers for ovarian cancer diagnosis and prognosis. Here, we determined the expression profiles of 43 plasma cytokines in ovarian cancer patients using this high throughput protein array technology developed in our laboratory. Materials and Methods: The expression of 43 cytokines from 13 ovarian cancer patients and 12 normal women was determined simultaneously using human cytokine antibody microarray technology. The differential expression of cytokines was analyzed using the Student's t-test and two-way hierarchical cluster analysis approach. Results: Our data showed that 22 cytokines were significantly increased in the plasma of ovarian cancer patients compared to normal women (t-test, two-tailed, p<0.05). The results from cytokine antibody array assays were in agreement with the published data, but also revealed a new group of cytokines whose expression levels were altered in ovarian cancer. Cluster analysis suggested an interesting link between cytokine profile and ovarian cancer. Conclusion: Human cytokine antibody arrays are a valuable tool to profile cytokine expression from patients' specimen. The cytokine profile may prove to be of diagnostic and prognostic significance in ovarian cancer.
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CANCER GENOMICS & PROTEOMICS 1: 9-16 (2004)
Detection of Chromosomal Aberrations in Transitional Cell Carcinoma of the Bladder by Representational Difference Analysis
OMAR MOUSSA1, GABOR SZALAI1, HASSAN ABOL-ENEIN2, NABIL K. BISSADA3, MOHAMED A. GHONEIM2, DENNIS K. WATSON1
1Department of Pathology and Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St. Charleston, SC 29425, U.S.A.
2Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt;
3Department of Urology, University of Arkansas, 800 Marshall Street, Slot840, Little Rock, AR 22202, U.S.A.
Abstract: Background: Transitional cell carcinoma (TCC) is the fifth most common solid malignancy in the U.S. Unfortunately, recurrence, invasion and metastasis are characteristic of bladder cancer. Additional studies to define factors involved in bladder cancer progression would facilitate the design of molecularly-based diagnostic and therapeutic approaches. Materials and Methods: Genomic alterations contribute to bladder cancer tumorigenesis. To identify gains or losses of chromosomal regions involved in invasive bladder cancer, we performed representational difference analysis (RDA) using DNA from transitional cell carcinoma (TCC) vs. DNA from adjacent non-tumor tissue. Results: Our genome-wide analysis allowed the identification of 61 loci that show loss or gain in bladder cancer. Many of the identified loci are present within large chromosomal regions previously found to undergo alterations in bladder cancer, as well as defining regions previously not associated with bladder cancer. Genomic changes identified by RDA are found in multiple tumors. Conclusion: Identification of gene losses and gains provides a means to uncover novel candidate tumor suppressor genes and oncogenes. RDA is a simple, inexpensive and efficient approach for the detection of specific gene changes in bladder cancer.
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CANCER GENOMICS & PROTEOMICS 1: 71-76 (2004)
Atomic Force Microscopy as a Tool in Nanobiology Part II: Force Spectroscopy in Genomics and Proteomics
LILIAN T. COSTA, STEFAN THALHAMMER, WOLFGANG M. HECKL
Department for Geo-and Environmental Sciences, GeobioCenter and Center for Nanoscience, Ludwig-Maximilians-University, Theresienstr. 41, 80333 Munich, Germany
Abstract: We present possible applications of Atomic Force Microscopy (AFM) as a force spectroscopy tool in genomics and proteomics. AFM applications in these fields have opened new opportunities for studying the mechanical properties of biomolecules and their interactions in their native environment, as well as in determining the binding affinity of DNA proteins in dependence with the target DNA sequence for further correlative studies on physical affinity and biological relevance of the controlled gene. Furthermore, force spectroscopy is a powerful analytical tool to investigate structural and functional features of biomolecules. Altogether, these tools have revealed useful application in genomics and proteomics.
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CANCER GENOMICS & PROTEOMICS 1: 39-44 (2004)
The X-chromosome RBMX Gene is Expressed in Mammary Carcinoma
F. GÏMEZ-ESQUER1, D. AGUDO1, F. MARTÉNEZ-ARRIBAS2, M.J. NUNEZ-VILLAR2, M. POLLÁN3, J. SCHNEIDER1,2
1Universidad Rey Juan Carlos, Facultad de Ciencias de la Salud, Madrid;
2Fundación Tejerina-Centro de Patología de la Mama, Madrid;
3Centro Nacional de Epidemiología, Madrid, Spain
Abstract: Background: A gene located on the q11.23 region of the male chromosome, RBMY, which plays a role in spermatogenesis, is down-regulated in testicular cancer. RBMY is a diverged X-Y shared gene. The corresponding X chromosome gene, RBMX, is located on Xq26. Materials and Methods: We studied fresh tissues from 122 infiltrating breast cancers (99 ductal infiltrating, 19 lobular infiltrating and 4 tubular carcinomas) for the expression of RBMX by means of differential RT-PCR (reverse transcription-polymerase chain reaction), using beta-actin as an internal control and normalization standard. The obtained results were compared with all available clinical and molecular data of the studied tumors (estrogen and progesterone receptors (ER & PR), c-erb-B2, p53, Ki67, DNA-ploidy, Bcl-2, VEGF, CD105 (endoglin), histologic variety, histologic and nuclear grade and axillary node invasion). Results: RBMX RT-PCR was successful in 120/122 instances. All 120 cases expressed RBMX. The only significant correlation found between RBMX expression and all the variables tested was an inverse one with CD105 (endoglin) mRNA-expression (r=-3063; p=0.0007). Conclusion: The X-chromosome RBMX gene is expressed in all breast cancers. The expression is inversely correlated with the expression of the angiogenesis-associated CD105 (endoglin) gene. The precise meaning of this association has still to be elucidated.
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CANCER GENOMICS & PROTEOMICS 1: 59-70 (2004)
Atomic Force Microscopy as a Tool in Nanobiology Part I: Imaging and Manipulation in Cytogenetics
STEFAN THALHAMMER, WOLFGANG M. HECKL
Department for Geo-and Environmental Sciences, GeoBioCenter and Center for Nanoscience, Ludwig-Maximilians-University, Theresienstr. 41, 80333 Munich, Germany
Abstract: Atomic force microscopy (AFM) nowadays can be used not only as a high-resolution imaging tool for precise cytogenetic studies but, at the same time, for mechanical measurements and manipulation of genetic material. This combination allows, for the first time, identification of the sample area, microdissection and nanoextraction of genetic material for further biomedical and biochemical studies. In this review, we examine AFM techniques like cutting, gripping and extracting biomaterial at the submicron scale under high-resolution image control and potential applications in cytogenetics.
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CANCER GENOMICS & PROTEOMICS 1: 45-52 (2004)
Application of Newly Developed Tissue-arrays to Study EMMPRIN (CD147) Expression in Malignant Non-Hodgkin Lymphoma
CHRISTOPH THORNS1, FRANK NOACK1, ALFRED C. FELLER1, HARTMUT MERZ1, WINFRIED STOCKER2, EWALD MUELLER-KUNERT2, HEINZ-WOLFRAM BERND1
1Department of Pathology, German Consultation and Reference Centre for Lymphomas, Medical University Luebeck;
2Euroimmun Medizinische Labordiagnostica AG, Luebeck, Germany
Abstract: Background: Matrix-metalloproteinases (MMP) are involved in a broad spectrum of physiological processes. Moreover, they also play a key role in tumour invasion and metastatic spread. The induction of MMPs is mediated via the extracellular matrix-metalloproteinase inducer (EMMPRIN). EMMPRIN is expressed in a variety of epithelial tumours, but expression in non-Hodgkin lymphomas has not been studied yet. Materials and Methods: Therefore we studied 201 non-Hodgkin lymphomas (NHL) for EMMPRIN expression by immunohistochemistry using a newly developed tissue microarray (TMA). This new approach to TMA-technology entails the great advantage that areas of interest (for instance with high tumour cell content) are selected by means of serial sections, thus maintaining appropriate samples of each case on the array. The samples were evaluated with regard to the number of positive tumour cells and staining intensity. Results: All specimens on the arrays contained a sufficient amount of tumour cells. Immunohistochemistry yielded satisfactory results in 196 out of 201 cases. EMMPRIN was expressed in a significantly higher number of tumour cells in high-grade NHL compared with low-grade NHL. Furthermore, the staining intensity was significantly stronger in high-grade NHL. Conclusion: We report on a new type of TMA that allows effective parallel analysis of a large number of tissue samples. Our data indicate that the expression of EMMPRIN is strongly associated with a more aggressive lymphoma type. However, additional studies are required to elucidate the role of EMMPRIN in the tumour biology of NHL. Possibly, EMMPRIN could be a new target in the therapy of NHL.
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CANCER GENOMICS & PROTEOMICS 1: 17-22 (2004)
Protein Expression Profiles Indicative for Drug Resistance of Kidney Carcinoma
THOMAS EFFERTH1, MANFRED VOLM2
1Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg;
2German Cancer Research Center, Heidelberg, Germany
Abstract: The purpose of this investigation was to evaluate whether different protein patterns exist between drug-sensitive and drug-resistant kidney carcinomas. As a first step, expressions of drug resistance proteins (P-glycoprotein (P-gp), glutathione S-transferase-ð (GST-ð), DNA topoisomerase IIá (Topo IIá), alkaline phosphatase (AP), catalase, thymidylate synthetase, metallothionein), signal transducers (protein kinase Cá/â (PKCá/â)), proliferation-associated proteins (Ki-67) and proteins of proto-oncogenes and tumor suppressors (ErbB1, ErbB2, Fos, Jun, Myc, Ras and p53) of primary cell cultures of human kidney carcinomas of 18 patients were determined. The expression levels of the proteins were compared with the response to doxorubicin, vincristine or mafosfamide measured by growth inhibition and nucleotide incorporation assays. As a second step, those proteins showing a relationship to doxorubicin resistance (P-gp, GST-ð, Topo IIá, PKCá/â, AP, ErbB1, ErbB2, Fos, K-Ras, p53, and Ki-67) were analyzed by hierarchical cluster analysis and clustered image mapping. The resulting clusters were correlated with the drug resistance data. The data shows that different protein expression profiles exist between drug-resistant and –sensitive kidney carcinoma cell cultures. Finally, the clustered image map (CIM) demonstrates a sensitive area that is characterized by a lower expression of proteins and a resistant area with a higher expression of proteins. These results may have important implications for the diagnosis and therapy of kidney cancer. The resistance proteins and the resistance-related factors found in the present analysis may be suitable parameters to predict treatment outcome of kidney cancer.
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CANCER GENOMICS & PROTEOMICS 1: 53-58 (2004)
Altered Levels of Cytochrome P450 Genes in Hepatitis B or C Virus-infected Liver Identified by Oligonucleotide Microarray
NORIO IIZUKA1,2, MASAAKI OKA1, YOSHIHIKO HAMAMOTO3, NAOHIDE MORI1, TAKAO TAMESA1, AKIRA TANGOKU1, TAKANOBU MIYAMOTO3, SHUNJI UCHIMURA3, HIRONOBU NAKAYAMA4, KENJI HAMADA4, HISAFUMI YAMADA-OKABE4
1Department of Surgery II and 2Department of Bioregulatory Function, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505;
3Department of Computer Science and Systems Engineering, Faculty of Engineering, Yamaguchi University, 2-16-1 Tokiwadai, Ube, Yamaguchi 755-8611;
4Pharmaceutical Research Department 4, Kamakaura Research Laboratories,Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
Abstract: Background: Molecular pathogenesis of hepatocellular carcinoma (HCC) remains to be clarified. Many studies with DNA chip technology have revealed altered levels of several cytochrome P450 (CYP) family genes in human HCC. However, little is known about their alterations in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-infected livers. Materials and Methods: We here used high-density oligonucleotide arrays to evaluate alterations of CYP genes in five of each HBV- or HCV-infected livers in comparison with six normal livers. We extracted the data of 32 CYP genes from those of 12600 genes. Results: Among these 32 CYPs, expression levels of four genes were insignificant. The expressions of CYP1B1 and CYP3A7 were up-regulated, whereas the expressions of 12 other CYPs, including CYP2A6, CYP2A7 and CYP2C19, were down-regulated in HBV- and/or HCV-infected livers compared with normal livers. Conclusion: These data will allow us to better understand the roles of CYPs in the pathogenesis of HBV- and HCV-related HCCs.
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CANCER GENOMICS & PROTEOMICS 1: 1-8 (2004)
Establishment and Validation of Quantitative Real-time PCR Assay for Aberrant Methylation of 14-3-3ó Gene in Breast and Lung Carcinoma
UBARADKA G. SATHYANARAYANA1,2, MAKOTO SUZUKI1, SHINICHI TOYOOKA1, ASHA PADAR1, KIYOMI O. TOYOOKA1, ANDREA L. ZERN1, KUNIHARU MIYAJIMA1, TAKASHI TAKAHASHI3, ELIZABETH BRAMBILLA4, ADI F. GAZDAR1,2
1Hamon Center for Therapeutic Oncology Research and
2Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, U.S.A.;
3Division of Molecular Oncology, Aichi Cancer Center, Nagoya 464-8681, Japan;
4Laboratoire de Pathologie Cellulaire, Centre Hospitalier Regional Universitaire, Grenoble 38043, France
Abstract: Background: 14-3-3ó gene has been shown to be responsible for G2 cell cycle checkpoint control by p53 in response to DNA damage in human cells. In order to increase the potential utility of 14-3-3ó gene as a molecular marker in tumor analysis and prognosis, we established and validated a quantitative real-time MSP assay and correlated our findings with the standard MSP assay. Materials and Methods: We examined the expression of 14-3-3ó gene by reverse transcription PCR (RT-PCR) in breast and lung cancer cell lines and control non-malignant tissue samples. To elucidate the mechanism of gene silencing, we studied the methylation patterns in cell lines, tumors and non-malignant control tissues of breast and lung using previously reported MSP assay. For fluorescence based quantitative Real-Time PCR assay, we designed primers and probe specific to 14-3-3ó gene, validated the assay in cell lines and non-malignant control tissues of breast and lung and extended the study to primary tumors and corresponding non-malignant tissues. Results: The concordances between the standard MSP assay and the real-time assay were 95-100%. The overall concordances between standard MSP and real-time assay in 60 cell lines were 97%. By real-time assay, the differences in methylation frequencies between malignant and non-malignant breast and between malignant and non-malignant lung tissues; between NSCLC and SCLC cell lines; between MSP (-) and MSP (+) samples and between MSP (+) and MSP (++) samples were statistically significant. The mean real-time values for MSP (-), MSP (+) and MSP (++) samples were 2, 28 and 53 respectively. Conclusion: We conclude that promoter methylation is a valid pathway for silencing of 14-3-3ó gene in primary breast and lung carcinomas. The real-time assay to distinguish the extent and degree of methylation of 14-3-3ó gene among malignant and non-malignant tissues would potentially enhance the utility of this marker in breast and lung cancer analysis and prognosis.
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CANCER GENOMICS & PROTEOMICS 1: 87-94 (2004)
Correlation Between Interferon Alpha Receptor Protein Expression and Sensitivity to Interferon Alpha Subtypes in Human Renal Carcinoma Cell Lines
TOSHIO ARIYASU1, NOBORU FUJIOKA1, SHIGETO YAMAMOTO1, YOSHIAKI YANAI1, HIROSHI YAMAUCHI1, HAKUO IKEGAMI1, MASAO IKEDA1, MASASHI KURIMOTO1, SHIGEO HORIE2, TADAICHI KITAMURA3
1Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., 675-1 Fujisaki, Okayama 702-8006;
2Department of Urology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605;
3Department of Urology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japan
Abstract: Background: We have previously characterized the antitumor activities and immunological properties of interferon-alpha (IFN-á) subtypes on renal cell carcinoma (RCC). However, the mechanism responsible for the different biologic activities among the IFN-á subtypes is still unclear. To explain the different cellular sensitivities to IFN-á subtypes, detailed expression of the interferon-alpha receptor (IFNAR)-1 and IFNAR-2 subunits on different RCC cell lines was examined and compared with sensitivity of the cell lines to the IFN-á subtypes. Materials and Methods: We investigated the antiproliferative effects of natural IFN-á subtypes (IFN-á2 and IFN-á8) using eight RCC cell lines. IFNAR-1 and IFNAR-2 expression were determined by RT-PCR and Western blotting. To determine a possible relationship between IFN activity and IFNAR expression, the correlation between the 50% effective IFN dose (ED50) for growth inhibition and the level of IFNAR expression was statistically examined. Results: We report here that IFN-á8 more potently induced growth inhibition than IFN-á2 in the majority of the RCC cell lines examined, this being in accordance with our previous results. The ED50 value of IFN-á8 was lower than 1000 (IU/ml) in six of the eight cell lines, whereas that of IFN-á2 was lower than 1000 (IU/ml) in three of the eight cell lines. The results of experiments using Western blotting analysis revealed that IFN-á subtype sensitivities were closely correlated with the expression level of IFNAR-2(c), a long form of the IFNAR-2 protein, in seven of the eight cell lines. Conclusion: These results suggest that the intensity of IFNAR-2(c) protein expression could be an important prognostic marker for clinical application of particular IFN-á subtypes in RCC.
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CANCER GENOMICS & PROTEOMICS 1: 33-38 (2004)
SMAD4-related Familial Juvenile Polyposis Syndrome with Colon Cancer
PHILIPPE MOGUELET1, LOUIS-FRANCOIS PLASSA2, JOSETTE MÅTAYER3, PAUL TÅNIERE4, SYLVIANE OLSCHWANG5, THIERRY FREBOURG6, MARTINE LEGRAND2, HUGUES DE THE2, ANNE JANIN1, PHILIPPE BERTHEAU1
1Service de Pathologie et INSERM ERM 0220 and 2Service de Biochimie Hopital Saint Louis AP-HP, 1 avenue Claude Vellefaux, 75010 Paris;
3Service de Pathologie, 4Service de Chirurgie Generale and
6Service de Genetique Medicale, CHU Hopital Charles Nicolle, 1 rue Germont, 76000 Rouen; 5Fondation Jean Dausset, CEPH, 27 rue Juliette Dodu, 75010 Paris, France
Abstract: Background: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract with an increased risk of malignancy. SMAD4 germline mutations account for about a third of JPS. Patients and Methods: We describe, in the same family, the morphological and genetic aspects of two cases of JPS with colon cancer in one patient. Results: Both cases were characterised by diffuse colorectal and gastric involvement by typical juvenile polyps as well as "atypical" multilobulated and densely epithelial polyps with some dysplastic areas. A germline mutation of SMAD4 was demonstrated in both cases. SMAD4 protein and DNA analyses were performed on the colonic adenocarcinoma showing a lack of expression of SMAD4 protein and loss of heterozygosity at the SMAD4 locus. Conclusion: These two exceptional familial cases underline the fact that the morphological features of JPS associated with SMAD4 mutations are different from those found in non SMAD4 mutated cases: polyps are more widespread in the upper GI tract with massive gastric polyposis and they have a dense epithelial component. This study also confirmed that SMAD4 genetic analysis is useful for the diagnosis of JPS and may be predictive of an increased risk of malignancy through inactivation of both alleles of SMAD4.
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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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