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Pospiech K, Płuciennik E, Bednarek AK. WWOX Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions. Front Oncol 2018; 8:345. [PMID: 30211123 PMCID: PMC6121138 DOI: 10.3389/fonc.2018.00345] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 08/06/2018] [Indexed: 11/18/2022] Open
Abstract
The WWOX tumor suppressor gene is located at 16q23. 1–23.2, which covers the region of FRA16D—a common fragile sites. Deletions within the WWOX coding sequence are observed in up to 80% of breast cancer cases, which makes it one of the most common genetic alterations in this tumor type. The WWOX gene is known to play a role in breast cancer: increased expression of WWOX inhibits cell proliferation in suspension, reduces tumor growth rates in xenographic transplants, but also enhances cell migration through the basal membrane and contributes to morphological changes in 3D matrix-based cell cultures. The WWOX protein may act in several ways, as it has three functional domains—two WW domains, responsible for protein-protein interactions and an SDR domain (short dehydrogenase/reductase domain) which catalyzes conversions of low molecular weight ligands, most likely steroids. In epithelial cells, WWOX modulates gene transcription through interaction with p73, AP-2γ, and ERBB4 proteins. In steroid hormone-regulated tissues like mammary gland epithelium, the WWOX SDR domain acts as a steroid dehydrogenase. The relationship between WWOX and hormone receptors was shown in an animal model, where WWOX(C3H)+/–mice exhibited loss of both ER and PR receptors. Moreover, in breast cancer specimens, a positive correlation was observed between WWOX expression and ER status. On the other hand, decreased WWOX expression was associated with worse prognosis, namely higher relapse and mortality rates in BC patients. Recently, it was shown that genomic instability might be driven by the loss of WWOX expression. It was reported that WWOX plays role in DNA damage response (DDR) and DNA repair by regulating ATM activation through physical interaction. A genome caretaker function has also been proposed for WWOX, as it was found that WWOX sufficiency decreases homology directed repair (HDR) and supports non-homologous end-joining (NHEJ) repair as the dominant DSB repair pathway by Brca1-Wwox interaction. In breast cancer cells, WWOX was also found to modulate the expression of glycolysis pathway genes, through hypoxia-inducible transcription factor 1α (HIF1α) regulation. The paper presents the current state of knowledge regarding the WWOX tumor suppressor gene in breast cancer, as well as future research perspectives.
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Affiliation(s)
- Karolina Pospiech
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Elzbieta Płuciennik
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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Abu-Remaileh M, Khalaileh A, Pikarsky E, Aqeilan RI. WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia. Cell Death Dis 2018; 9:511. [PMID: 29724996 PMCID: PMC5938702 DOI: 10.1038/s41419-018-0510-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/13/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022]
Abstract
Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox ΔHep ) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Proliferation
- Diet, High-Fat/adverse effects
- Diethylnitrosamine/pharmacology
- Digoxin/pharmacology
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Hepatocytes/drug effects
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lymphatic Metastasis
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Prognosis
- Signal Transduction
- Tumor Burden/drug effects
- Tumor Suppressor Proteins/deficiency
- Tumor Suppressor Proteins/genetics
- WW Domain-Containing Oxidoreductase/deficiency
- WW Domain-Containing Oxidoreductase/genetics
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Affiliation(s)
- Muhannad Abu-Remaileh
- The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Abed Khalaileh
- Department of Surgery, Hebrew University-Hadassah Medical, Jerusalem, Israel
| | - Eli Pikarsky
- The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Rami I Aqeilan
- The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
- Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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Mahas A, Potluri K, Kent MN, Naik S, Markey M. Copy number variation in archival melanoma biopsies versus benign melanocytic lesions. Cancer Biomark 2017; 16:575-97. [PMID: 27002761 DOI: 10.3233/cbm-160600] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations. OBJECTIVE This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi. METHODS Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi. RESULTS We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis. CONCLUSIONS Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.
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Affiliation(s)
- Ahmed Mahas
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | - Keerti Potluri
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | - Michael N Kent
- Department of Dermatology, Wright State University Boonshoft School of Medicine, Dayton, OH, USA.,Dermatopathology Laboratory of Central States, Dayton, OH, USA
| | - Sameep Naik
- Dermatopathology Laboratory of Central States, Dayton, OH, USA
| | - Michael Markey
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
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Zhang Y, Tang ET, Du Z. Detection of MET Gene Copy Number in Cancer Samples Using the Droplet Digital PCR Method. PLoS One 2016; 11:e0146784. [PMID: 26765781 PMCID: PMC4713204 DOI: 10.1371/journal.pone.0146784] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 12/22/2015] [Indexed: 11/18/2022] Open
Abstract
PURPOSE The analysis of MET gene copy number (CN) has been considered to be a potential biomarker to predict the response to MET-targeted therapies in various cancers. However, the current standard methods to determine MET CN are SNP 6.0 in the genomic DNA of cancer cell lines and fluorescence in situ hybridization (FISH) in tumor models, respectively, which are costly and require advanced technical skills and result in relatively subjective judgments. Therefore, we employed a novel method, droplet digital PCR (ddPCR), to determine the MET gene copy number with high accuracy and precision. METHODS The genomic DNA of cancer cell lines or tumor models were tested and compared with the MET gene CN and MET/CEN-7 ratio determined by SNP 6.0 and FISH, respectively. RESULTS In cell lines, the linear association of the MET CN detected by ddPCR and SNP 6.0 is strong (Pearson correlation = 0.867). In tumor models, the MET CN detected by ddPCR was significantly different between the MET gene amplification and non-amplification groups according to FISH (mean: 15.4 vs 2.1; P = 0.044). Given that MET gene amplification is defined as MET CN >5.5 by ddPCR, the concordance rate between ddPCR and FISH was 98.0%, and Cohen's kappa coefficient was 0.760 (95% CI, 0.498-1.000; P <0.001). CONCLUSIONS The results demonstrated that the ddPCR method has the potential to quantify the MET gene copy number with high precision and accuracy as compared with the results from SNP 6.0 and FISH in cancer cell lines and tumor samples, respectively.
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Affiliation(s)
- Yanni Zhang
- Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China
| | - En-Tzu Tang
- Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China
| | - Zhiqiang Du
- Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China
- * E-mail:
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Harutyunyan T, Hovhannisyan G, Babayan N, Othman MA, Liehr T, Aroutiounian R. Influence of aflatoxin B1 on copy number variants in human leukocytes in vitro. Mol Cytogenet 2015; 8:25. [PMID: 25901182 PMCID: PMC4404608 DOI: 10.1186/s13039-015-0131-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/25/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus spec. The latter are worldwide contaminants of food with mutagenic and carcinogenic activities in animals and humans. AFB1 was shown to have deleterious effects on metabolism of eukaryotes in many model systems, including the ability to inhibit DNA replication. An agent that disturbs DNA replication may also have the potential to induce de novo DNA copy number variations (CNVs). RESULTS Blood samples of three clinically healthy carriers were treated in vitro with AFB1 and chromosome preparations were subjected to parental origin determination fluorescence in situ hybridization (pod-FISH). Probes able to visualize CNVs in 8p21.2 and 15q11.2 were applied. In this setting here for the first time an influence of AFB1 on molecular-cytogenetically detectable CNVs could be shown. CONCLUSIONS The obtained results indicate that: (i) pod-FISH is a single cell directed, sensitive and suitable method for the analysis of mutagen induced CNVs, (ii) AFB1 has the potential to induce in vitro instability of known CNVs in human leukocytes.
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Affiliation(s)
- Tigran Harutyunyan
- Department of Genetics and Cytology, Yerevan State University, 1 Alex Manoogian, 0025 Yerevan, Armenia
| | - Galina Hovhannisyan
- Department of Genetics and Cytology, Yerevan State University, 1 Alex Manoogian, 0025 Yerevan, Armenia
| | - Nelly Babayan
- Department of Genetics and Cytology, Yerevan State University, 1 Alex Manoogian, 0025 Yerevan, Armenia ; Institute of Molecular Biology, National Academy of Sciences, 7 Hasratyan, 0014 Yerevan, Armenia
| | - Moneeb Ak Othman
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, Jena, D-07743 Germany
| | - Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, Jena, D-07743 Germany
| | - Rouben Aroutiounian
- Department of Genetics and Cytology, Yerevan State University, 1 Alex Manoogian, 0025 Yerevan, Armenia
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Baryła I, Styczeń-Binkowska E, Bednarek AK. Alteration of WWOX in human cancer: a clinical view. Exp Biol Med (Maywood) 2015; 240:305-14. [PMID: 25681467 DOI: 10.1177/1535370214561953] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
WWOX gene is located in FRA16D, the highly affected chromosomal fragile site. Its tumor suppressor activity has been proposed on a basis of numerous genomic alterations reported in chromosome 16q23.3-24.1 locus. WWOX is affected in many cancers, showing as high as 80% loss of heterozygosity in breast tumors. Unlike most tumor suppressors impairing of both alleles of WWOX is very rare. Despite cellular and animal models information on a WWOX role in cancer tissue is limited and sometimes confusing. This review summarizes information on WWOX in human tumors.
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Affiliation(s)
- Izabela Baryła
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland
| | - Ewa Styczeń-Binkowska
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland
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Liu M, Li Y, Chen L, Chan THM, Song Y, Fu L, Zeng TT, Dai YD, Zhu YH, Li Y, Chen J, Yuan YF, Guan XY. Allele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma. Gastroenterology 2014; 146:1084-96. [PMID: 24417816 DOI: 10.1053/j.gastro.2013.12.041] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 12/08/2013] [Accepted: 12/20/2013] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Although there are a few highly penetrant mutations that are linked directly to cancer initiation, more less-penetrant susceptibility alleles have been associated with cancer risk and progression. We used RNA sequence analysis to search for genetic variations associated with pathogenesis of hepatocellular carcinoma (HCC). METHODS We analyzed 400 paired HCC and adjacent nontumor tissues, along with clinical information, from patients who underwent surgery at Sun Yat-Sen University in Guangzhou, China. Total RNA was extracted from tissues and sequenced, and variations with allele imbalance were identified. Effects of variants on cell functions were investigated in HCC cell lines and tumor xenografts in mice. Variants were associated with patient outcomes. RESULTS We found a high proportion of allele imbalance in genes related to cellular stress. A nucleotide variation in the Oxidative Stress-Induced Growth Inhibitor 1 (OSGIN1) gene (nt 1494: G-A) resulted in an amino acid substitution (codon 438: Arg-His). The variant form of OSGIN1 was specifically retained in the tumor tissues. Functional assays showed that the common form of OSGIN1 functioned as a tumor suppressor, sensitizing HCC cells to chemotherapeutic agents by inducing apoptosis. However, the variant form of OSGIN1 was less effective. It appeared to affect the translocation of OSGIN1 from the nucleus to mitochondria, which is important for its apoptotic function. The expression pattern and localization of OSGIN1 was altered in HCC specimens, compared with adjacent liver tissue. Levels of OSGIN1 messenger RNA were reduced in 24.7% of HCC specimens, and down-regulation was associated with shorter overall and disease-free survival times of patients. Patients with the OSGIN1 1494A variant had the shortest mean survival time (32.68 mo) among patient subgroups, and their tumor samples had the lowest apoptotic index. CONCLUSIONS We identified OSGIN1 as a tumor suppressor that is down-regulated or altered in human HCCs. Variants of OSGIN1 detected in HCC samples reduce apoptosis and are associated with shorter survival times of patients.
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Affiliation(s)
- Ming Liu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Yan Li
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Tim Hon Man Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Yangyang Song
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Li Fu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Ting-Ting Zeng
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yong-Dong Dai
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ying-Hui Zhu
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yan Li
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Juan Chen
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Yun-Fei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations. Cancers (Basel) 2014; 6:79-111. [PMID: 24419005 PMCID: PMC3980619 DOI: 10.3390/cancers6010079] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/24/2013] [Accepted: 01/03/2014] [Indexed: 12/14/2022] Open
Abstract
The liver acts as a hub for metabolic reactions to keep a homeostatic balance during development and growth. The process of liver cancer development, although poorly understood, is related to different etiologic factors like toxins, alcohol, or viral infection. At the molecular level, liver cancer is characterized by a disruption of cell cycle regulation through many molecular mechanisms. In this review, we focus on the mechanisms underlying the lack of regulation of the cell cycle during liver cancer, focusing mainly on hepatocellular carcinoma (HCC). We also provide a brief summary of novel therapies connected to cell cycle regulation.
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Yu YP, Song C, Tseng G, Ren BG, LaFramboise W, Michalopoulos G, Nelson J, Luo JH. Genome abnormalities precede prostate cancer and predict clinical relapse. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:2240-2248. [PMID: 22569189 PMCID: PMC3385611 DOI: 10.1016/j.ajpath.2012.03.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Revised: 01/26/2012] [Accepted: 03/01/2012] [Indexed: 12/25/2022]
Abstract
The prediction of prostate cancer clinical outcome remains a major challenge after the diagnosis, even with improved early detection by prostate-specific antigen (PSA) monitoring. To evaluate whether copy number variation (CNV) of the genomes in prostate cancer tumor, in benign prostate tissues adjacent to the tumor (AT), and in the blood of patients with prostate cancer predicts biochemical (PSA) relapse and the kinetics of relapse, 241 samples (104 tumor, 49 matched AT, 85 matched blood, and 3 cell lines) were analyzed using Affymetrix SNP 6.0 chips. By using gene-specific CNV from tumor, the genome model correctly predicted 73% (receiver operating characteristic P = 0.003) cases for relapse and 75% (P < 0.001) cases for short PSA doubling time (PSADT, <4 months). The gene-specific CNV model from AT correctly predicted 67% (P = 0.041) cases for relapse and 77% (P = 0.015) cases for short PSADT. By using median-sized CNV from blood, the genome model correctly predicted 81% (P < 0.001) cases for relapse and 69% (P = 0.001) cases for short PSADT. By using median-sized CNV from tumor, the genome model correctly predicted 75% (P < 0.001) cases for relapse and 80% (P < 0.001) cases for short PSADT. For the first time, our analysis indicates that genomic abnormalities in either benign or malignant tissues are predictive of the clinical outcome of a malignancy.
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Affiliation(s)
- Yan P. Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Chi Song
- Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - George Tseng
- Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Bao Guo Ren
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - William LaFramboise
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - George Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Joel Nelson
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Yu J, Wang YJ, Gao YT, Shi WX, Wang QH, Liu T, Xu YJ, Yang B, Du Z. Detection of HCC-associated gene expression by real-time fluorescence quantitative PCR to establish a molecular diagnostic index for HCC. Shijie Huaren Xiaohua Zazhi 2011; 19:588-595. [DOI: 10.11569/wcjd.v19.i6.588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a molecular diagnostic index for hepatocellular carcinoma (HCC).
METHODS: The expression of 11 genes was assessed by real-time fluorescent quantitative polymerase chain reaction (QRT-PCR) in 40 HCC specimens and matched tumor-adjacent specimens and surgical margin specimens, 10 cirrhotic tissue specimens, and 10 normal liver tissue specimens. Using G3PDH as a control, the 2-ΔΔCT method was used to calculate the relative gene expression levels. HCC-associated genes were then selected to establish a molecular diagnostic model for HCC.
RESULTS: Compared with normal liver tissue specimens, approximately 65.0%, 75.0%, and 67.5% of HCC specimens showed a >3-fold increase in the expression levels of tumor suppressor genes PRDM2, IGFBP3, and DLC-1, and approximately 87.5%, 77.5%, 82.5%, 85.0%, and 67.5% of HCC specimens showed a >3-fold decrease in the expression levels of oncogenes GPC3, STMN, CCNA2, BIRC5, and AFP, respectively. The expression levels of these eight genes differed significantly between HCC and cirrhotic tissue (0.45 ± 0.69 vs 0.50 ± 0.20; 0.17 ± 0.20 vs 0.67 ± 0.47; 0.29 ± 0.48 vs 0.58 ± 0.60; 677.57 ± 999.30 vs 4.41 ± 3.99; 17.56 ± 28.28 vs 1.17 ± 1.08; 53.17 ± 103.64 vs 2.09 ± 1.50; 16.53 ± 16.39 vs 1.82 ± 1.39; 4445.70 ± 11642.87 vs 0.86 ± 0.43, all P < 0.05). Molecular diagnostic index was estimated based on these eight genes, which was 2.2 ± 1.5, 3.0 ± 1.6, 2.9 ± 1.5, 6.3 ± 1.2 for liver cirrhosis, surgical margin, tumor-adjacent tissue, and cancer tissue, respectively. The molecular diagnostic index for cancer tissue was significantly different from those for liver cirrhosis, surgical margin, and tumor-adjacent tissue. When a molecular diagnostic index of 4 or greater was adopted to diagnose liver cancer using liver cirrhosis as a control, the sensitivity, specificity, and the area under the receiving operative curve (ROC) were 100%, 90%, and 0.995, respectively.
CONCLUSION: A molecular diagnostic index for HCC was successfully established using fluorescence quantitative PCR to detect HCC-associated genes.
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Żelazowski MJ, Płuciennik E, Pasz-Walczak G, Potemski P, Kordek R, Bednarek AK. WWOX expression in colorectal cancer--a real-time quantitative RT-PCR study. Tumour Biol 2011; 32:551-60. [PMID: 21347750 PMCID: PMC3093543 DOI: 10.1007/s13277-010-0150-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Accepted: 12/14/2010] [Indexed: 01/16/2023] Open
Abstract
The WWOX gene is a tumour suppressor gene affected in various types of malignancies. Numerous studies showed either loss or reduction of the WWOX expression in variety of tumours, including breast, ovary, liver, stomach and pancreas. Recent study demonstrated that breast cancer patients exhibiting higher WWOX expression showed significantly longer disease-free survival in contrast to the group with lower relative WWOX level. This work was undertaken to show whether similar phenomena take place in colon tumours and cell lines. To assess the correlation of WWOX gene expression with prognosis and cancer recurrence in 99 colorectal cancer patients, we performed qRT-PCR analysis. We also performed analysis of WWOX promoter methylation status using MethylScreen method and analysis of loss of heterozygosity (LOH) status at two WWOX-related loci, previously shown to be frequently deleted in various types of tumours. A significantly better disease-free survival was observed among patients with tumours exhibiting high level of WWOX (hazard ratio = 0.39; p = 0.0452; Mantel-Cox log-rank test), but in multivariate analysis it was not an independent prognostic factor. We also found that although in colorectal cancer WWOX expression varies among patients and correlates with DFS, the exact mode of decrease in this type of tumour was not found. We failed to find the evidence of LOH in WWOX region, or hypermethylation in promoter regions of this gene. Although we provide the evidence for tumour-suppressive role of WWOX gene expression in colon, we were unable to identify the molecular mechanism responsible for this.
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Affiliation(s)
- Maciej Jakub Żelazowski
- Department of Molecular Carcinogenesis, Medical University of Łódź, Zeligowskiego Str 7/9, 90-752 Łódź, Poland.
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Abstract
Hepatocellular carcinoma (HCC) is the most frequent tumour derived from the malignant transformation of hepatocytes. It is well established that cancer is a disease of the genome and, as in other types of solid tumours, a large number of genetic and epigenetic alterations are accumulated during the hepatocarcinogenesis process. Recent developments using comprehensive genomic tools have enabled the identification of the molecular diversity in human HCC. Consequently, several molecular classifications have been described using different approaches and important progress has been made particularly with the transcriptomic, genetic, chromosomal, miRNA and methylation profiling. On the whole, all these molecular classifications are related and one of the major determinants of the identified subgroups of tumours are gene mutations found in oncogenes and tumour suppressors. However, the full understanding of the HCC molecular classification requires additional comprehensive studies using both genomic and pathway analyses. Finally, a refinement of the molecular classification of HCC, taking into account the geographical and genetic diversity of the patients, will be essential for an efficient design of the forthcoming personalized clinical treatments.
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Affiliation(s)
- Jessica Zucman-Rossi
- Inserm, U674, Génomique fonctionnelle des tumeurs solides, F-75010 Paris, France.
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13
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Loss expression of active fragile sites genes associated with the severity of breast epithelial abnormalities. Chin Med J (Engl) 2008. [DOI: 10.1097/00029330-200810020-00004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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Aderca I, Moser CD, Veerasamy M, Bani-Hani AH, Bonilla-Guerrero R, Ahmed K, Shire A, Cazanave SC, Montoya DP, Mettler TA, Burgart LJ, Nagorney DM, Thibodeau SN, Cunningham JM, Lai JP, Roberts LR. The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX. J Hepatol 2008; 49:373-83. [PMID: 18620777 PMCID: PMC2574998 DOI: 10.1016/j.jhep.2008.05.015] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2007] [Revised: 04/23/2008] [Accepted: 05/18/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. METHODS Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. RESULTS Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. CONCLUSIONS WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.
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Affiliation(s)
- Ileana Aderca
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Catherine D. Moser
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Manivannan Veerasamy
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
- Department of Internal Medicine, Grand Rapids Medical Education & Research Center / Michigan State University, Grand Rapids, MI, USA
| | - Ahmad H. Bani-Hani
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Ruben Bonilla-Guerrero
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Kadra Ahmed
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Abdirashid Shire
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Sophie C. Cazanave
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Damian P. Montoya
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Teresa A. Mettler
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Lawrence J. Burgart
- Division of Anatomic Pathology, University of Minnesota College of Medicine and Abbott Northwestern Hospital, Minneapolis, MN, USA
| | - David M. Nagorney
- Division of Gastroenterologic and General Surgery, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Stephen N. Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Julie M. Cunningham
- Department of Laboratory Medicine and Pathology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Jin-Ping Lai
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Lewis R. Roberts
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
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15
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Wang M, Gu J, Wang Y, Gong B. Loss of WWOX expression in human extrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol 2008; 135:39-44. [PMID: 18629536 DOI: 10.1007/s00432-008-0449-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2007] [Accepted: 06/21/2008] [Indexed: 12/01/2022]
Abstract
OBJECTIVES WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1. To investigate the role of the WWOX gene in the development of extrahepatic cholangiocarcinoma (ECC), 30 tissue samples of ECC were examined. METHODS Loss of heterozygosity (LOH), real time reverse transcription PCR (RT-PCR), and immunohistochemistry were used to assess the role of WWOX in cholangiocarcinoma. RESULTS LOH was observed in 50% of cases, loss of mRNA was observed in 46.67% of the cases and loss of WWOX protein expression was found in 56.67% of ECC tissue samples. LOH, mRNA, and protein expression had a significant correlation with histological grading. The correlation coefficients were -0.623, -0.475 and -0.543, respectively. However, WWOX expression had no correlations with other clinicopathological factors such as age, gender, clinical staging or the status of preoperative hepatic function (p > 0.05). Poorly differentiated ECC had significantly lower expression of WWOX than that of moderately or well differentiated ones (p < 0.05). CONCLUSIONS Loss of WWOX may be involved in the tumorigenesis of extrahepati cholangiocarcinoma.
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Affiliation(s)
- Mei Wang
- Department of Oncology, Changhai Hospital, 200433, Shanghai, China
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16
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Abstract
A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.
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17
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Zucman-Rossi J, Laurent-Puig P. Genetic diversity of hepatocellular carcinomas and its potential impact on targeted therapies. Pharmacogenomics 2008; 8:997-1003. [PMID: 17716233 DOI: 10.2217/14622416.8.8.997] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide and represents the third cause of mortality among deaths from cancer. It has been extensively studied in terms of genetic alteration in the last 10 years and our knowledge has dramatically increased in this field, leading to the definition of different altered pathways in hepatocarcinogenesis. Recently, a comprehensive study of genetic and transcriptomic alterations in a large series of HCC tumors enabled the identification of a six-group molecular-based classification of HCC, defined by a simple 16-gene signature. This classification is closely related to specific alteration of WNT and AKT oncogenic pathways. Together with the analysis of defined oncogenic proteins, such global classifications could be useful in the prediction of future-targeted therapy efficiency.
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18
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Chang NS, Hsu LJ, Lin YS, Lai FJ, Sheu HM. WW domain-containing oxidoreductase: a candidate tumor suppressor. Trends Mol Med 2006; 13:12-22. [PMID: 17142102 DOI: 10.1016/j.molmed.2006.11.006] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2006] [Revised: 11/03/2006] [Accepted: 11/22/2006] [Indexed: 10/23/2022]
Abstract
Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others. Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown. We propose that suppression of WWOX expression by overexpressed hyaluronidases might contribute in part to the development of hormone independence in invasive cancer.
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Affiliation(s)
- Nan-Shan Chang
- Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China.
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19
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Abstract
Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1alpha (HNF1alpha) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/beta-catenin pathway through CTNNB1/beta-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently beta-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.
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Affiliation(s)
- P Laurent-Puig
- Inserm, U775, Bases Moléculaires de la réponse aux xénobiotiques, Paris, France
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20
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O'Keefe LV, Richards RI. Common chromosomal fragile sites and cancer: focus on FRA16D. Cancer Lett 2005; 232:37-47. [PMID: 16242840 DOI: 10.1016/j.canlet.2005.07.041] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2005] [Accepted: 07/30/2005] [Indexed: 11/19/2022]
Abstract
A growing body of experimental evidence supports the view that certain human chromosomal fragile sites have roles to play in cancer. The principle lines of evidence are at the level of mutation mechanism and gene function. Most research in this area has previously focussed on the FRA3B common fragile site and the FHIT gene that spans this site. Here we review recent progress in characterising the second most readily observed common fragile site, FRA16D, and the WWOX gene that spans it. Comparative analyses of FRA3B/FHIT and FRA16D/WWOX reveal some striking similarities suggesting that these sites and their associated genes may play a part in a normal protective response of cells to environmental stress.
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Affiliation(s)
- Louise V O'Keefe
- ARC Special Research Centre for the Molecular Genetics of Development, ARC-NHMRC Research Network in Genes and Environment in Development, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide S.A. 5005, Australia
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21
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O'Keefe LV, Liu Y, Perkins A, Dayan S, Saint R, Richards RI. FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila. Oncogene 2005; 24:6590-6. [PMID: 16007179 DOI: 10.1038/sj.onc.1208806] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Fragile sites are chromosomal structures that have been proposed to have a determining role in cancer-associated DNA instability. The human WWOX gene spans the FRA16D chromosomal fragile site, the common minimal region of homozygous deletion found in adenocarcinomas and three out of five translocation breakpoints in multiple myeloma. Transcripts from the alternatively spliced WWOX gene encode proteins with common N-terminal WW domains and variable homology to the oxidoreductase family of proteins. In this study, the Drosophila orthologue of the WWOX gene was identified and subjected to mutagenesis via homologous recombination. The resultant DmWWOX1 mutants were viable but exhibited an increased sensitivity to ionizing radiation. This radiation sensitivity was rescued by reintroduction and expression of either the wild-type Drosophila or human WWOX genes. Thus, the protective function of DmWWOX in response to irradiation in Drosophila is conserved with human WWOX (hWWOX). This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression.
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Affiliation(s)
- Louise V O'Keefe
- ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide, Adelaide, SA 5005, Australia
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22
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Aqeilan RI, Kuroki T, Pekarsky Y, Albagha O, Trapasso F, Baffa R, Huebner K, Edmonds P, Croce CM. Loss of WWOX expression in gastric carcinoma. Clin Cancer Res 2004; 10:3053-8. [PMID: 15131042 DOI: 10.1158/1078-0432.ccr-03-0594] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox. EXPERIMENTAL DESIGN Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer. A total of 81 primary gastric adenocarcinoma were analyzed. RESULTS Loss of heterozygosity was observed in 31% of the cases and loss of Wwox protein expression was found in 65% of gastric adenocarcinoma primary specimens and 33% of gastric cancer cell lines. In addition, we found a high correlation between Wwox and Fhit protein expression. CONCLUSIONS Our results indicate that alterations of the WWOX gene may be involved quite frequently in gastric tumorigenesis. Our data could be used in future studies to develop diagnostic and targeted therapy of stomach cancer.
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Affiliation(s)
- Rami I Aqeilan
- Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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23
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Watson JEV, Kamkar S, James K, Kowbel D, Andaya A, Paris PL, Simko J, Carroll P, McAlhany S, Rowley D, Collins C. Molecular analysis of WFDC1/ps20 gene in prostate cancer. Prostate 2004; 61:192-9. [PMID: 15305342 DOI: 10.1002/pros.20100] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND WFDC1/ps20 protein has been previously established as a growth suppressor of the prostate cancer cell line PC3. It maps to chromosome 16q23.1, a region of frequent loss of heterozygosity, familial association, and genomic loss in prostate cancer. We, therefore, chose to examine WFDC1/ps20 for mutations and expression changes in prostate cancer. METHODS DNA from 21 prostate cancer patients and 5 prostate cancer cell lines was screened for mutations in the WFDC1/ps20 gene by sequencing PCR products of each exon. An SphI polymorphism in the 5' UTR was screened in 23 tumors, 22 normal adjacent prostate tissue samples, and 35 control DNAs. Expression of WFDC1/ps20 in different tissue types was examined by Northern blot and by PCR across a multi-tissue cDNA panel. Expression patterns of WFDC1/ps20 in primary tumors were examined by full-length RT-PCR and products were cloned and sequenced to identify novel splice forms. Quantitative RT-PCR analysis of WFDC1/ps20 was performed in a separate cohort of matched tumor/benign tissues. RESULTS No tumor-associated mutations were identified in the coding region of WFDC1/ps20. A novel polymorphism was found in exon 6 in DNA from cell lines, tumors, and normal adjacent benign tissue. A novel splice form completely deleted for exon 3 was found in tumor and normal prostate RNA. Quantitative RT-PCR demonstrated significant down regulation of WFDC1/ps20 in prostate tumors. Subdivision of normal tissue into stromal and epithelial compartments showed that WFDC1/ps20 expression correlates exponentially with the amount of stroma present. CONCLUSIONS WFDC1/ps20 is down regulated but not frequently mutated in prostate cancer. It is expressed predominantly in the normal stroma of the prostate. We, therefore, propose that WFDC1/ps20 may not be a classical tumor suppressor gene, but might play a role in the maintenance of the normal extra cellular matrix milieu in the prostate.
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Affiliation(s)
- J E Vivienne Watson
- Comprehensive Cancer Center, University of California, San Francisco, California, USA
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24
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Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol 2004; 68:1003-15. [PMID: 15313394 DOI: 10.1016/j.bcp.2004.05.029] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2004] [Accepted: 05/10/2004] [Indexed: 01/18/2023]
Abstract
Strong evidence emphasizes the role of the insulin-like growth factor (IGF) system and of type-I IGF receptor (IGF-IR) signalling in tumourigenesis. In this connection: (i) changes in the expression pattern of components of the IGF system (autocrine/paracrine expression of IGF-I and -II, overexpression of IGF-IR, decreased expression of IGF-binding proteins (IGFBPs) and of type-II IGF receptor/cation-independent mannose-6-phosphate receptor (IGF-II/M6PR) and (ii) increased serum concentrations of proteases that cleave the IGFBPs (e.g., cathepsin D) were observed in patients with hepatocellular carcinomas (HCC), in human hepatoma cell lines and in their conditioned culture medium, as well as in rodent models of hepatocarcinogenesis. Accordingly, studies carried out with animal models do suggest that the IGF system and IGF-IR signalling may play a role in hepatocarcinogenesis and in deregulated proliferation and apoptosis of HCC cells. Finally the instrumental role of Raf/MEK/ERK, one of the signalling cascades stimulated by IGF-IR, in anthracycline-induced apoptosis of HepG2 and Huh-7 human hepatoma cell lines emphasizes that care must be taken when designing combinations of antitumoural molecules for antineoplastic treatment. This review addresses the putative roles of the IGF system in primary HCC, with a special focus on the underlying molecular mechanisms. In a second part it emphasizes the putative interference of IGF-IR signalling with chemotherapeutic drug-induced apoptosis in human hepatoma cells.
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Affiliation(s)
- Catherine Alexia
- Inserm U.481, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP416, 75870 Paris Cédex 18, France
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25
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Park SW, Ludes-Meyers J, Zimonjic DB, Durkin ME, Popescu NC, Aldaz CM. Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma. Br J Cancer 2004; 91:753-9. [PMID: 15266310 PMCID: PMC2364795 DOI: 10.1038/sj.bjc.6602023] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The WWOX (WW-domain containing oxidoreductase) is a candidate tumour suppressor gene spanning the same chromosome region, 16q23, as the second most common fragile site (FS), FRA16D. Deletions detected by comparative genomic hybridisation (CGH) and loss of heterozygosity at microsatellite markers on chromosome 16q are common in many human cancers including hepatocellular carcinoma (HCC). The development of human HCC is closely associated with exposure to oncogenic viruses and chemical carcinogens, agents known to frequently target common FS. We examined the status of WWOX genomic DNA, RNA and protein in 18 cell lines derived from human HCC and found recurrent alterations of the gene. Loss of DNA copy-number confined to band 16q23 was detected by CGH in several cell lines. Although homozygous deletions of the WWOX gene were not detected, WWOX mRNA expression was absent or lower in 60% of cell lines. The occurrence of aberrant WWOX reverse transcription–PCR products with deletion of exons 6–8 correlated significantly with altered WWOX expression. All of the cell lines showing mRNA downregulation had a decreased or undetectable level of WWOX protein as demonstrated by Western blotting with antibody to WWOX. Furthermore, 13 out of the 18 cell lines expressed decreased levels or no WWOX protein when compared with normal liver. These results show that WWOX gene is frequently altered in HCC and raise the possibility that this gene is implicated in hepatocarcinogenesis.
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Affiliation(s)
- S-W Park
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4262, USA
| | - J Ludes-Meyers
- Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - D B Zimonjic
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4262, USA
| | - M E Durkin
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4262, USA
| | - N C Popescu
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4262, USA
- 37 Convent Drive MSC 4262, Building 37, Room 4128B, Bethesda, MD 20892-4262, USA. E-mail:
| | - C M Aldaz
- Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
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Rozier L, El-Achkar E, Apiou F, Debatisse M. Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer. Oncogene 2004; 23:6872-80. [PMID: 15286716 DOI: 10.1038/sj.onc.1207809] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Fragile sites are classified as common or rare depending on their occurrence in the populations. While rare sites are mainly associated with inherited diseases, common sites have been involved in somatic rearrangements found in the chromosomes of cancer cells. Here we study a mouse locus containing the ionotropic glutamate receptor delta 2 (grid2) gene in which spontaneous chromosome rearrangements occur frequently, giving rise to mutant animals in inbred populations. We identify and clone common fragile sites overlapping the mouse grid2 gene and its human ortholog GRID2, lying respectively at bands 6C1 and 4q22 in a 7-Mb-long region of synteny. These results show a third example of orthologous common sites conserved at the molecular level, and reveal an unexpected link between an inherited disease and an aphidicolin-sensitive region. Recurrent deletions of subregions of band 4q22 have been previously described in human hepatocellular carcinomas. This 15-Mb-long region appears precisely centered on the site described here, which strongly suggests that it also plays a specific role in hepatic carcinogenesis.
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Affiliation(s)
- Lorène Rozier
- Instabilité du génome et cancer, FRE2584-CNRS, Institut Curie, 26 rue d'Ulm 75248 Paris Cédex 05, France
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27
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Zhu GN, Zuo L, Zhou Q, Zhang SM, Zhu HQ, Gui SY, Wang Y. Loss of heterozygosity on chromosome 10q22-10q23 and 22q11.2-22q12.1 and p53 gene in primary hepatocellular carcinoma. World J Gastroenterol 2004; 10:1975-8. [PMID: 15222050 PMCID: PMC4572244 DOI: 10.3748/wjg.v10.i13.1975] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To analyze loss of heterozygosity (LOH) and homozygous deletion on p53 gene (exon2-3, 4 and 11), chromosome 10q22-10q23 and 22q11.2-22q12.1 in human hepatocellular carcinoma (HCC).
METHODS: PCR and PCR-based microsatellite polymorphism analysis techniques were used.
RESULTS: LOH was observed at D10S579 (10q22-10q23) in 4 of 20 tumors (20%), at D22S421 (22q11.2-22q12.1) in 3 of 20 (15%), at TP53.A (p53 gene exon 2-3) in 4 of 20 (20%), at TP53.B (p53 gene exon 4) in 6 of 20 (30%), and at TP53.G (p53 gene exon 11) in 0 of 20 (0%). Homozygous deletion was detected at 10q22-10q23 (8/20; 40%), 22q11.2-22q12.1 (8/20; 40%), p53 gene exon 2-3 (0/20;0%), p53 gene exon 4 (6/20; 30%), and p53 gene exon 11 (2/20; 10%).
CONCLUSION: There might be unidentified tumor suppressor genes on chromosome 10q22-10q23 and 22q11.2-22q12.1 that contribute to the pathogenesis and development of HCC.
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Affiliation(s)
- Guang-Neng Zhu
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei 230032, Anhui Province, China
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28
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Wang F, Denison S, Lai JP, Philips LA, Montoya D, Kock N, Schüle B, Klein C, Shridhar V, Roberts LR, Smith DI. Parkin gene alterations in hepatocellular carcinoma. Genes Chromosomes Cancer 2004; 40:85-96. [PMID: 15101042 DOI: 10.1002/gcc.20020] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The Parkin gene is an extremely large gene (1.5 Mb) within the highly unstable FRA6E common fragile site (CFS) region, which is frequently altered in ovarian, breast, and hepatocellular carcinomas. Because Parkin/FRA6E has genomic similarities to FHIT/FRA3B and WWOX/FRA16D, two other large tumor-suppressor genes that are within CFS regions, we were interested in characterizing Parkin gene alterations and their possible association with cancer. After analyzing 50 cancer-derived cell lines including 11 hepatocellular carcinoma (HCC) cell lines, we found that one HCC cell line, PLC/PRF/5, had a detectable homozygous deletion encompassing exon 3. Using quantitative duplex PCR and fluorescence in situ hybridization analysis to characterize the copy number changes of Parkin exons in HCC cell lines, we found that 4 of 11 HCC cell lines had heterozygous deletions of Parkin exons and one, Hep3B, had an exon duplication. Parkin protein expression was significantly decreased or absent in all 11 HCC cell lines. Furthermore, more than 50% of HCC primary tumors had decreased Parkin expression compared to that in normal liver tissue. Parkin gene-transfected PLC5 and Hep3B cells grew more slowly than vector-only transfectants and also showed increased sensitivity to apoptosis induced by cell-cycle inhibitors. Therefore, we suggest that Parkin may be involved in tumor suppression and that the loss of Parkin contributes to the development of hepatocarcinoma.
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Affiliation(s)
- Fang Wang
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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29
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Liu D, Wada I, Tateno H, Ogino D, Suzuki M, Li L, Lu W, Kojiro M, Fukayama M, Okabe H, Fukumoto M. Allelotypic Characteristics of Thorotrast-Induced Intrahepatic Cholangiocarcinoma: Comparison to Liver Cancers not Associated with Thorotrast. Radiat Res 2004; 161:235-43. [PMID: 14731065 DOI: 10.1667/rr3118] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
To elucidate the genetic alterations that are specific to Thorotrast-induced liver cancers and their possible roles in tumorigenesis, we analyzed loss of heterozygosity (LOH) at 37 loci. Our previous study of liver cancers that were not associated with Thorotrast found LOH at 9 of these loci to be characteristic of intrahepatic cholangiocarcinoma (ICC), at 19 to be characteristic of hepatocellular carcinoma (HCC), and at 9 to be common to both ICC and HCC. LOH analysis was also performed in tissues of cholangiolocellular carcinoma, which is thought to originate from a common stem cell progenitor of hepatocytes and bile duct epithelial cells. We found frequent LOH at D4S1538, D16S2624 and D17S1303 to be common to all the subtypes of liver cancers, independent of the specific carcinogenic agent. In contrast, LOH at D4S1652 generally was not observed in Thorotrast-induced ICC. LOH analysis revealed that Thorotrast-induced ICC shares some LOH features with both ICC and HCC that were not induced by Thorotrast; however, it is more similar to ICC than to HCC in terms of genetic changes. This study could narrow down the crucial chromosomal loci whose deletions are relevant to hepatobiliary carcinogenesis irrespective of the carcinogenic agent. The study of LOH at loci other the those crucial ones may help us understand how the phenotype of liver cancers is determined.
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Affiliation(s)
- Duo Liu
- Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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Chen ST, Chuang JI, Wang JP, Tsai MS, Li H, Chang NS. Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system. Neuroscience 2004; 124:831-9. [PMID: 15026124 DOI: 10.1016/j.neuroscience.2003.12.036] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2003] [Indexed: 11/21/2022]
Abstract
WW domain-containing oxidoreductase WOX1, also known as WWOX or FOR, is a proapoptotic protein and a putative tumor suppressor. Hyaluronidases such as PH-20, Hyal-1 and Hyal-2 induce the expression of WOX1, and hyaluronidases and hyaluronan are involved in the embryonic development. In the present study, we document the expression of WOX1 in the developing murine nervous system. Immunohistochemical analysis revealed that WOX1 was differentially expressed in early dividing cells from all three germ layers from embryonic to perinatal stages. In murine fetuses, WOX1 was present prevalently in the brainstem, spinal cord and peripheral nerve bundles, but its expression decreased after birth. In parallel, the expression of WOX1, as determined by Western blotting, was significantly reduced in the brain stem and spinal cord of adult mice. Notably, high levels of WOX1 immunoreactivity was observed in the neural crest-derived structures such as cranial and spinal ganglia and cranial mesenchyme during the late fetal stage. In the adult brain, WOX1 is abundant in the epithelial cells of the choroids plexus and ependymal cells, while a low to moderate level of WOX1 is observed within white matter tracts, such as axonal profiles of the corpus callosum, striatum, optic tract, and cerebral peduncle. WOX1 is shown to mediate apoptosis synergistically with p53 in vitro. Nonetheless, the expression profiles of WOX1 were found to be similar in both p53 wild type and knockout mice, suggesting that WOX1 expression is not controlled by p53-mediated gene transcription. Taken together, in this study we have shown the expression and distribution of WOX1 in developing and adult murine nervous system. The potential role of WOX1 in the neuronal differentiation is discussed.
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Affiliation(s)
- S T Chen
- Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 701, Taiwan, ROC.
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Chang NS, Doherty J, Ensign A, Lewis J, Heath J, Schultz L, Chen ST, Oppermann U. Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochem Pharmacol 2003; 66:1347-54. [PMID: 14555208 DOI: 10.1016/s0006-2952(03)00484-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Human WWOX gene encodes a putative tumor suppressor WW domain-containing oxidoreductase WOX1 (also known as WWOX or FOR). A high frequency of loss of heterozygosity (LOH) of this gene has been shown in prostate, lung, breast and other cancers. In addition, numerous aberrant WWOX mRNA transcripts have been found in cancer cells. WOX1 is a proapoptotic protein. In response to stress or apoptotic stimuli, WOX1 became phosphorylated at Tyr33, which enabled its complex formation with activated p53 and JNK1. The p53/WOX1 complex translocated to the mitochondria and further to the nuclei to mediate apoptosis. WOX1 mutants, which were inactivated for nuclear translocation or Tyr33 phosphorylation, failed to induce apoptosis, indicating that activation of WOX1 via Tyr33 phosphorylation, followed by nuclear translocation, is essential for inducing cell death. WOX1 induced apoptosis synergistically with p53. In contrast, transiently activated JNK1 induced anti-apoptotic response, and this protective activity inhibited WOX1-induced apoptosis. Taken together, WOX1 is involved in stress and apoptotic responses, and is likely to regulate the activation of both p53 and JNK1.
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Affiliation(s)
- Nan-Shan Chang
- Laboratory of Molecular Immunology, Guthrie Research Institute, 1 Guthrie Square, Sayre, PA 18840, USA.
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32
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Large-scale sequencing analysis of the full-length cDNA library of human hepatocellular carcinoma. J Biomed Sci 2003. [DOI: 10.1007/bf02256314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P, Buendia MA. Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features. Hepatology 2002; 36:692-701. [PMID: 12198663 DOI: 10.1053/jhep.2002.35342] [Citation(s) in RCA: 130] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
E-cadherin is a key cell adhesion protein implicated as a tumor/invasion suppressor in human carcinomas and a binding partner of beta-catenin, which plays a critical role in Wnt signaling and in tumorigenesis. Here we report genetic and expression studies of E-cadherin and beta-catenin in hepatocellular carcinoma (HCC). Immunohistochemical analysis of E-cadherin expression in 37 HCCs and adjacent nontumor tissues revealed important variations among tumor samples, ranging from complete or heterogeneous down-regulation in 35% of cases to marked overexpression in 40% of tumors. Loss of E-cadherin expression was closely associated with loss of heterozygosity (LOH) at the E-cadherin locus and methylation of CpG islands in the promoter region (P <.002), predominantly in hepatitis B virus (HBV)-related tumors (P <.005). No mutation of the E-cadherin gene could be detected in the tumors examined, suggesting the requirement for reversible mechanisms of E-cadherin down-regulation. In most HCCs, including E-cadherin-positive and -negative cases, beta-catenin was strongly expressed at the cell membrane and nuclear accumulation of the protein was correlated with the presence of mutations in the beta-catenin gene itself, but not with E-cadherin loss. At difference with a number of epithelial cancers, vascular invasion was frequently noted in HCCs showing enforced expression of the membranous E-cadherin/beta-catenin complex. In conclusion, these data support the notion that E-cadherin might play diverse and seemingly paradoxic roles in HCC, reflecting specific requirements for tumor growth and spread in the liver environment.
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Affiliation(s)
- Yu Wei
- Unité de Recombinaison et Expression Génétique (Inserm U163), Institut Pasteur, Paris, France
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Blons H, Laccourreye O, Houllier AM, Carnot F, Brasnu D, Beaune P, Zucman-Rossi J, Laurent-Puig P. Delineation and candidate gene mutation screening of the 18q22 minimal region of deletion in head and neck squamous cell carcinoma. Oncogene 2002; 21:5016-23. [PMID: 12118382 DOI: 10.1038/sj.onc.1205626] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2002] [Revised: 04/05/2002] [Accepted: 04/26/2002] [Indexed: 11/09/2022]
Abstract
The 18q chromosome arm is frequently lost in advanced head and neck squamous cell carcinoma. Twenty-four microsatellite markers located on chromosome 18q were genotyped in 145 primary tumors and 10 cell lines in order to identify putative tumor suppressor genes implicated in tumor progression. Two different minimal common regions of loss (MCRL) were identified at 18q22 and 18q23 respectively. To refine and delineate boundaries of an homozygous deletion found in one cell line, 44 extra markers located at 18q22 were analysed and the homozygous deletion was precisely defined within a critical region of 4.9 Mb. Four known genes (CDH7, CDH19, DNAM-1, FLJ23594) located in this critical region and two EST clusters (Hs.96900, Hs.98628) were selected for further investigations. For these six genes, genomic structures were established, somatic mutations were screened in 20 HNSCC and 10 cell lines and transcription levels were determined in eight cell lines. No somatic mutations were found in any of the candidate genes analysed (57 coding exons). However, differential transcription levels were observed for CDH19 and Hs.96900 in head and neck cancer cell lines supporting their putative involvement through down regulation mechanisms in head and neck cancer progression.
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Affiliation(s)
- Hélène Blons
- Unité de Toxicologie Moléculaire, U490 INSERM, 45 Rue des Saints Pères 75006 Paris, France
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Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002; 21:2593-604. [PMID: 11971194 DOI: 10.1038/sj.onc.1205434] [Citation(s) in RCA: 243] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2001] [Revised: 02/15/2002] [Accepted: 02/21/2002] [Indexed: 01/06/2023]
Abstract
The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene amplification of selected oncogenes. The changes observed in different HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation. An understanding of the molecular pathogenesis of HCC may provide new markers for tumor staging, for assessment of the relative risk of tumor formation, and open new opportunities for therapeutic intervention.
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Affiliation(s)
- Mark A Feitelson
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
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Abstract
In 1979, the first chromosome alteration associated with familial cancer was reported. Five years later, a fragile site was observed in the same chromosome region. The product of the fragile histidine triad (FHIT) gene, which encompasses this fragile site, is partially or entirely lost in most human cancers, indicating that it has a tumour-suppressor function. Inactivation of only one FHIT allele compromises this suppressor function, indicating that a 'one-hit' mechanism of tumorigenesis is operative. Are genes disrupted at other fragile sites? And, are these genes also tumour suppressors?
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MESH Headings
- Acid Anhydride Hydrolases
- Adult
- Alleles
- Amino Acid Motifs
- Animals
- Apoptosis/genetics
- Cell Transformation, Neoplastic/genetics
- Chromosome Breakage
- Chromosome Fragile Sites
- Chromosome Fragility/genetics
- Chromosomes, Human, Pair 3/genetics
- Chromosomes, Human, Pair 3/ultrastructure
- Chromosomes, Human, Pair 8/genetics
- Chromosomes, Human, Pair 8/ultrastructure
- Conserved Sequence
- DNA Replication
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/prevention & control
- Forecasting
- Gastrointestinal Neoplasms/chemically induced
- Gastrointestinal Neoplasms/genetics
- Gene Deletion
- Genes, Tumor Suppressor
- Genetic Predisposition to Disease
- Genetic Therapy
- Humans
- Kidney Neoplasms/genetics
- Mice
- Mice, Knockout
- Models, Genetic
- Neoplasm Proteins/chemistry
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Recombination, Genetic
- Structure-Activity Relationship
- Translocation, Genetic
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Affiliation(s)
- K Huebner
- Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
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