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Silencing of tissue factor pathway inhibitor‐2 gene in malignant melanomas
Author(s) -
Nobeyama Yoshimasa,
OkochiTakada Eriko,
Furuta Junichi,
Miyagi Yohei,
Kikuchi Kanako,
Yamamoto Akifumi,
Nakanishi Yukihiro,
Nakagawa Hidemi,
Ushijima Toshikazu
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22637
Subject(s) - demethylating agent , cancer research , melanoma , gene silencing , biology , methylation , dna methylation , cpg site , microbiology and biotechnology , gene , gene expression , genetics
To identify tumor‐suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5‐aza‐2′‐deoxycytidine (5‐aza‐dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV‐I, MeWo and WM‐115. Seventy‐nine known genes with CGIs were identified as being upregulated (≥16‐fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI‐2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5‐aza‐dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI‐2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) ( p = 0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI‐2. The results showed that TFPI‐2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis. © 2007 Wiley‐Liss, Inc.