Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers.
Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers.
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发表时间：
1999-02
期刊：
影响因子：
11.2
通讯作者：
K. Bachman;J. Herman;P. Corn;A. Merlo;J. Costello;W. Cavenee;S. Baylin;J. Graff;J. Graff
中科院分区：
文献类型：
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作者：
K. Bachman;J. Herman;P. Corn;A. Merlo;J. Costello;W. Cavenee;S. Baylin;J. Graff;J. Graff
金属蛋白酶组织抑制因子-3(TIMP-3)可拮抗基质金属蛋白酶活性，抑制肿瘤生长、血管生成、侵袭和转移。TIMP-3的缺失与肿瘤的发生有关。在此，我们发现TIMP-3在人类癌症细胞系中与异常的启动子区域甲基化有关。经5-氮-2‘-脱氧胞苷介导的TIMP-3近端启动子区域去甲基化后，TIMP-3的表达恢复。基因组测序显示TIMP-3沉默与甲基化总密度有关，TIMP-3 CpG岛上的离散区域可能对该基因的沉默起重要作用。TIMP-3的异常甲基化发生在原发性肾癌、脑癌、结肠癌、乳腺癌和肺癌中，但在41例正常组织样本中均未发现。最常见的TIMP-3甲基化是在肾癌中发现的，肾癌起源于通常表达最高TIMP-3水平的组织。这种甲基化与这些肿瘤中缺乏可检测到的TIMP-3蛋白有关。总之，这些数据表明，TIMP-3的甲基化相关失活在许多人类肿瘤中很常见。
Tissue inhibitor of metalloproteinase-3 (TIMP-3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastasis. Loss of TIMP-3 has been related to the acquisition of tumorigenesis. Herein, we show that TIMP-3 is silenced in association with aberrant promoter-region methylation in cell lines derived from human cancers. TIMP-3 expression was restored after 5-aza-2'deoxycytidine-mediated demethylation of the TIMP-3 proximal promoter region. Genomic bisulfite sequencing revealed that TIMP-3 silencing was related to the overall density of methylation and that discrete regions within the TIMP-3 CpG island may be important for the silencing of this gene. Aberrant methylation of TIMP-3 occurred in primary cancers of the kidney, brain, colon, breast, and lung, but not in any of 41 normal tissue samples. The most frequent TIMP-3 methylation was found in renal cancers, which originate in the tissue that normally expresses the highest TIMP-3 levels. This methylation correlated with a lack of detectable TIMP-3 protein in these tumors. Together, these data show that methylation-associated inactivation of TIMP-3 is frequent in many human tumors.