Chromate exposure induces DNA hypermethylation of the mismatch repair gene MLH1 in lung cancer |
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Authors: | Mitsuhiro Tsuboi Kazuya Kondo Shiho Soejima Koichiro Kajiura Naoya Kawakita Hiroaki Toba Yukikiyo Kawakami Mitsuteru Yoshida Hiromitsu Takizawa Akira Tangoku |
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Affiliation: | 1. Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan;2. Department of Oncological Medical Services, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan |
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Abstract: | Hexavalent chromium is recognized as a human carcinogen. Our previous studies revealed that lung cancer (LC) in chromate-exposed workers (chromate LC) had molecular features of frequent microsatellite instability (MSI), repression of MLH1 level, and aberrant DNA methylation of several tumor-suppressor genes, including MLH1. In the present study, we quantitatively investigated MLH1-promoter methylation status using bisulfite pyrosequencing of paired tumorous/nontumorous tissues from chromate and nonchromate LCs to determine the effect of chromate exposure on MLH1-promoter methylation. The methylation level of MLH1 promoter was significantly higher in chromate LC tumors (P < .001) than nonchromate LC tumors and, among chromate LC, significantly higher in tumorous tissue than nontumorous tissue (P = .004). Moreover, the methylation level of MLH1 promoter in normal lung tissue tended to be higher in chromate LC than nonchromate LC (P = .062). In addition, LC with reduced levels of MLH1 showed significantly higher methylation levels of MLH1 promoter than LC exhibiting normal MLH1 levels (P = .019). Moreover, immunohistochemical analyses determined that levels of SUV39H1, an H3K9me2-related methyltransferase, were higher in chromate LC than nonchromate LC (P = .076). Furthermore, we evaluated three DNA double-strand break-repair genes (MRE11, RAD50, and DNA-PKcs) as possible targets of MSI by fragment-length polymorphism analysis, revealing the mutation frequency of RAD50 as significantly higher in chromate LC than nonchromate LC (P = .047). These results suggest that chromate exposure might induce MLH1 hypermethylation in LC as a mechanism of chromate-induced carcinogenesis. |
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Keywords: | chromium DNA methylation microsatellite instability MLH1 pyrosequencing |
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