RRC ID 42399
著者 Taniguchi H, Yamamoto H, Hirata T, Miyamoto N, Oki M, Nosho K, Adachi Y, Endo T, Imai K, Shinomura Y.
タイトル Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers.
ジャーナル Oncogene
Abstract Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Wnt antagonists have recently attracted wide attention. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind to Wnt proteins directly and inhibit Wnt signaling pathway. It has been reported that WIF-1 expression is down regulated in several solid tumors and that WIF-1 is silenced by promoter hypermethylation in lung and colorectal cancer. By using RT-PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas. Downregulation of WIF-1 mRNA expression was observed in 61 (91.0%) of 67 cancer cell lines, 16 (80.0%) of 20 esophageal, 23 (74.2%) of 31 gastric, 41 (82.0%) of 50 colorectal, and six (75.0%) of eight pancreatic cancer tissues. Downregulation of WIF-1 expression was also observed at protein level. No significant association between WIF-1 downregulation and clinicopathological characteristics was found, suggesting that downregulation of WIF-1 expression is an early event in carcinogenesis of these cancers. Indeed, downregulation of WIF-1 expression was observed in 32 (72.7%) of 44 colorectal adenoma tissues and 18 (78.2%) of 23 early mucosal or submucosal colorectal carcinoma tissues. CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues. Treatment with demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines. A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene. Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar. TOPflash assay showed WIF-1 inhibits Wnt canonical signaling in these cell lines. These results suggest tumor suppressive function of WIF-1, due to its ability to inhibit Wnt signaling. Our results suggest that WIF-1 silencing due to promoter hypermethylation is an important mechanism underlying aberrant activation of the Wnt signaling pathway in carcinogenesis of the digestive organs. Modulation of the Wnt pathway, through reversal of WIF-1 silencing by demethylating agents, is a potential target for treatment and/or prevention of gastrointestinal cancers.
巻・号 24(53)
ページ 7946-52
公開日 2005-11-24
DOI 10.1038/sj.onc.1208910
PII 1208910
PMID 16007117
MeSH Adaptor Proteins, Signal Transducing Carrier Proteins / biosynthesis* Carrier Proteins / genetics* Carrier Proteins / physiology Cell Transformation, Neoplastic / genetics* DNA Methylation Down-Regulation* Epigenesis, Genetic Gastrointestinal Neoplasms / genetics* Gastrointestinal Neoplasms / physiopathology Gene Expression Profiling Gene Silencing* Humans Promoter Regions, Genetic Repressor Proteins / biosynthesis* Repressor Proteins / genetics* Repressor Proteins / physiology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Up-Regulation
IF 7.971
引用数 148
WOS 分野 GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY ONCOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 TGBC1TKB(RCB1129) TGBC2TKB(RCB1130) TGBC18TKB(RCB1169) HHUA(RCB0658)