Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5'-CpG island in human gastric cancer cell lines
✍ Scribed by Shin Hyeok Kang; Hyun Ho Choi; Sang Gyun Kim; Hyun-Soon Jong; Noe Kyeong Kim; Seong-Jin Kim; Yung-Jue Bang
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- French
- Weight
- 87 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
The tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently cloned member of TIMP gene family, has been implicated in the negative regulation of tumor cell invasion and tumor growth. Down-regulation of this gene has been shown to occur in a mouse carcinogenesis model, suggesting that it might play a role in the tumor progression of some cancers. In this study, we used human gastric cancer cell lines to investigate whether TIMP-3 gene expression is suppressed in human gastric cancer. We examined whether aberrant DNA methylation of the 5-CpG island of the TIMP-3 gene is involved in this cancer. Nine of 10 human gastric cancer cell lines completely lost TIMP-3 gene expression compared with normal samples. Southern blot analysis and bisulfite genomic sequencing revealed aberrant hypermethylation near the transcription-start site of the TIMP-3 gene in all cell lines lacking TIMP-3 expression. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine restored TIMP-3 gene expression. Our results suggest that the TIMP-3 gene is another early target of tumor-associated aberrant DNA methylation in human gastric carcinogenesis. Consequently, genetic silencing of TIMP-3 may lead to a more malignant and invasive phenotype in these cancer cells. Int.