Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies
| Autor: | Malcolm V. Brock, Stephen B. Baylin, Yoshimitsu Akiyama, James G. Herman, Rainhardt Osieka, Hiromu Suzuki, Manel Esteller, Oliver Galm |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Lymphoma Biology medicine.disease_cause chemistry.chemical_compound Cell Line Tumor hemic and lymphatic diseases Genetics medicine Humans Epigenetics Promoter Regions Genetic Molecular Biology Tissue Inhibitor of Metalloproteinase-2 Methylation DNA Methylation medicine.disease Immunohistochemistry Hematopoiesis Demethylating agent Non-Hodgkin's lymphoma Enzyme Activation Leukemia chemistry DNA methylation Cancer research Carcinogenesis |
| Zdroj: | Oncogene. 24:4799-4805 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1208599 |
| Popis: | The tissue inhibitor of metalloproteinases-2 (TIMP-2) is known to antagonize matrix metalloproteinase activity and to suppress tumor growth, angiogenesis, invasion and metastasis. We analysed the methylation status of the CpG island in the TIMP-2 promoter region by methylation-specific polymerase chain reaction (MSP) in hematopoietic cell lines. TIMP-2 promoter hypermethylation in the lymphoma cell line Raji and the leukemia cell line KG1a was associated with transcriptional repression. Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in TIMP-2 upregulation in both cell lines. TIMP-2 was expressed in the cell lines HL60, U266 and XG1, which carry an unmethylated promoter region. MSP analysis of primary patient samples revealed aberrant methylation of TIMP-2 in 33/90 (36.7%) cases of non-Hodgkin's lymphoma (NHL), but not in normal peripheral blood lymphocytes as well as in nonmalignant bone marrow and lymph nodes. The frequency of TIMP-2 methylation was slightly higher in aggressive NHL subtypes compared to those with an indolent subtype (38.6 versus 33.3%). In contrast, TIMP-2 was not hypermethylated in any of the 40 cases of acute myelogenous leukemia examined. We conclude that promoter hypermethylation of TIMP-2 is a novel epigenetic event in the pathogenesis of lymphoid malignancies and may contribute to a more aggressive NHL phenotype. |
| Databáze: | OpenAIRE |
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