Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies
Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies
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DOI：
10.1038/sj.onc.1208599
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发表时间：
2005-07-14
期刊：
影响因子：
8
通讯作者：
Herman, JG
中科院分区：
文献类型：
--
作者：
Galm, O;Suzuki, H;Herman, JG
金属蛋白酶组织抑制剂 2 (TIMP-2) 已知可拮抗基质金属蛋白酶活性并抑制肿瘤生长、血管生成、侵袭和转移。我们通过甲基化特异性聚合酶链式反应 (MSP) 分析了造血细胞系中 TIMP-2 启动子区域 CpG 岛的甲基化状态。淋巴瘤细胞系 Raji 和白血病细胞系 KG1a 中的 TIMP-2 启动子高甲基化与转录抑制相关。用去甲基化剂 5-aza-2'-deoxycytidine 处理会导致两种细胞系中 TIMP-2 上调。 TIMP-2 在细胞系 HL60、U266 和 XG1 中表达，这些细胞系携带未甲基化的启动子区域。对主要患者样本的 MSP 分析显示，在 33/90 (36.7%) 的非霍奇金淋巴瘤 (NHL) 病例中，TIMP-2 存在异常甲基化，但在正常外周血淋巴细胞以及非恶性骨髓和淋巴结中则没有异常甲基化。与惰性亚型相比，侵袭性 NHL 亚型中 TIMP-2 甲基化的频率略高（38.6% vs 33.3%）。相比之下，在所检查的 40 例急性髓性白血病病例中，TIMP-2 均未出现高甲基化。我们得出的结论是，TIMP-2 启动子高甲基化是淋巴恶性肿瘤发病机制中的一个新的表观遗传事件，可能导致更具侵袭性的 NHL 表型。
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.