論文 - 詳細
| RRC ID | 42615 |
|---|---|
| 著者 | Cui X, Wakai T, Shirai Y, Yokoyama N, Hatakeyama K, Hirano S. |
| タイトル | Arsenic trioxide inhibits DNA methyltransferase and restores methylation-silenced genes in human liver cancer cells. |
| ジャーナル | Hum Pathol |
| Abstract |
In the present study, we investigated methylation status of the CpG islands of some major tumor suppressor genes both in human hepatocellular carcinoma and liver cancer cell lines and examined whether demethylation by arsenic trioxide (As2O3) could restore their expression in the cell lines. HepG2 and Huh-7 cells were treated with 2 to 10 micromol/L of AS2O3 and/or 1 micromol/L of 5-aza-2'-deoxycytidine for 24, 48, and 72 hours. The methylation status of the CpG island around the promoter regions of p161NK4a, RASSF1A, E cadherin, and GSTP1 was detected by a methylation-specific polymerase chain reaction (MSP). The messenger RNA (mRNA) and protein levels of these genes were determined by quantitative real-time reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemical analyses. The DNA methyltransferase (DNMT) mRNA levels and enzyme activity were also examined. The hypermethylated status of the promoter regions of p16INK4a, RASSF1A, E cadherin, and GSTP1 was observed in 10 (40%), 14 (56%), 6 (24%), and 12 (48%) of 25 patients with hepatocellular carcinoma, respectively. CpG methylation of the p16INK4a, RASSF1A, E cadherin, and GSTP1 genes was correlated to the reduction of mRNA levels in the cell lines, and mRNA expression of these 4 genes were indeed restored by low concentrations (2-6 micromol/L) of As2O3 through demethylation, as well as 1 micromol/L of 5-aza-2'-deoxycytidine. Western blot and immunohistochemical analyses confirmed that each protein was markedly enhanced after treatment with a low concentration of As2O3. In contrast, As2O3 at a high concentration (10 micromol/L) damaged cell membranes and remarkably suppressed these 4 protein levels. As2O3 decreased the mRNA expression of DNMT 1 and also dose-dependently inhibited DNMT activity. In conclusion, a low concentration of As2O3 induces CpG island demethylation of tumor suppressor genes by inhibition of DNMT and reactivates the partially/fully silenced genes in liver cancer cells. |
| 巻・号 | 37(3) |
| ページ | 298-311 |
| 公開日 | 2006-3-1 |
| DOI | 10.1016/j.humpath.2005.10.013 |
| PII | S0046-8177(05)00606-4 |
| PMID | 16613325 |
| MeSH | Aged Antineoplastic Agents / pharmacology* Arsenic Trioxide Arsenicals / pharmacology* Cadherins / genetics Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / enzymology Carcinoma, Hepatocellular / genetics Cell Line, Tumor DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors* DNA (Cytosine-5-)-Methyltransferases / metabolism DNA Methylation / drug effects Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Female Gene Expression Regulation, Neoplastic / drug effects* Gene Silencing / drug effects* Genes, Neoplasm / drug effects Genes, p16 / drug effects Glutathione S-Transferase pi / genetics Hepatocytes / drug effects Hepatocytes / enzymology Hepatocytes / pathology Humans Liver Neoplasms / drug therapy Liver Neoplasms / enzymology Liver Neoplasms / genetics* Male Middle Aged Oxides / pharmacology* RNA, Messenger / metabolism Tumor Suppressor Proteins / genetics |
| IF | 2.735 |
| 引用数 | 95 |
| WOS 分野 | PATHOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | |