論文 - 詳細
| RRC ID | 37614 |
|---|---|
| 著者 | Yu J, Cheng YY, Tao Q, Cheung KF, Lam CN, Geng H, Tian LW, Wong YP, Tong JH, Ying JM, Jin H, To KF, Chan FK, Sung JJ. |
| タイトル | Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. |
| ジャーナル | Gastroenterology |
| Abstract |
BACKGROUND & AIMS:By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. METHODS:Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. RESULTS:PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. CONCLUSIONS:PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor. |
| 巻・号 | 136(2) |
| ページ | 640-51.e1 |
| 公開日 | 2009-2-1 |
| DOI | 10.1053/j.gastro.2008.10.050 |
| PII | S0016-5085(08)01888-X |
| PMID | 19084528 |
| MeSH | Adenocarcinoma / diagnosis* Adenocarcinoma / genetics* Adenocarcinoma / metabolism Adult Aged Aged, 80 and over Animals Apoptosis / physiology Biomarkers, Tumor / metabolism Cadherins / genetics* Cadherins / metabolism* Case-Control Studies Cell Line, Tumor Cell Movement / physiology Cell Proliferation DNA Methylation / physiology* Female Gastric Mucosa / metabolism Humans Kaplan-Meier Estimate Male Mice Mice, Nude Middle Aged Multivariate Analysis Neoplasm Staging Precancerous Conditions / diagnosis Precancerous Conditions / genetics Precancerous Conditions / metabolism Prognosis Protocadherins Stomach / pathology Stomach / physiopathology Stomach Neoplasms / diagnosis* Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism Transplantation, Heterologous |
| IF | 17.373 |
| 引用数 | 152 |
| WOS 分野 | GASTROENTEROLOGY & HEPATOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | |