RRC ID 44613
著者 Ooki A, Yamashita K, Yamaguchi K, Mondal A, Nishimiya H, Watanabe M.
タイトル DNA damage-inducible gene, reprimo functions as a tumor suppressor and is suppressed by promoter methylation in gastric cancer.
ジャーナル Mol Cancer Res
Abstract In several types of human cancer, the gene expression of Reprimo, a highly glycosylated protein, is frequently silenced via methylation of its promoter. The aim of this study was to characterize the epigenetic inactivation of Reprimo and its biologic function and clinical relevance in gastric cancer. The correlation between Reprimo methylation and clinical relevance was assessed in 83 primary human gastric cancer tissues. The effects of Reprimo expression were also examined using in vitro and in vivo assays. Reprimo methylation was cancer specific and frequently observed. In two gastric cancer cell lines without Reprimo methylation, we observed faint or weak Reprimo expression under normal conditions and high expression under DNA-damaging conditions. In four gastric cancer cell lines with Reprimo methylation, however, Reprimo expression remained faint even under DNA-damaging conditions, with expression being restored in combination with agents that induce demethylation. Enforced Reprimo expression robustly inhibited cell proliferation and anchorage-independent colony formation and enhanced DNA damage-induced apoptosis. Inverse effects were observed via siRNA-mediated knockdown of endogenous Reprimo. Reprimo expression inhibited tumorigenesis in vivo. Reprimo methylation was also associated with a poor response in patients with gastric cancer treated with chemotherapy (P¼ 0.028), and a poor prognosis in patients with advanced gastric cancer (P¼ 0.03). In conclusion, Reprimo expression is normally induced in response to DNA damage, acting as a novel tumor suppressor in gastric cancer. However, Reprimo methylation abrogates its expression and effects. The clinical assessment of Reprimo promoter methylation may serve not only as a predictive marker for chemotherapy, but also as a marker for tumor aggressiveness.
巻・号 11(11)
ページ 1362-74
公開日 2013-11-1
DOI 10.1158/1541-7786.MCR-13-0091
PII 1541-7786.MCR-13-0091
PMID 23982217
MeSH Adult Aged Animals Antineoplastic Agents / pharmacology Biomarkers, Tumor Cell Cycle Proteins / genetics* Cell Cycle Proteins / metabolism Cell Line, Tumor Cisplatin / pharmacology Female Fluorouracil / pharmacology Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Glycoproteins / genetics* Glycoproteins / metabolism Humans Male Methylation Mice, Inbred BALB C Mice, Nude Middle Aged Promoter Regions, Genetic* Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Xenograft Model Antitumor Assays
IF 4.63
引用数 24
WOS 分野 ONCOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 GCIY(RCB0555) Kato III(RCB2088) MKN74(RCB1002) NUGC-4(RCB1939)