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- Title
Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors.
- Authors
Hironobu Sato; Hiromu Suzuki; Minoru Toyota; Masanori Nojima; Reo Maruyama; Shigeru Sasaki; Hideyasu Takagi; Yohei Sogabe; Yasushi Sasaki; Masashi Idogawa; Tomoko Sonoda; Mitsuru Mori; Kohzoh Imai; Takashi Tokino; Yasuhisa Shinomura
- Abstract
Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5ⲠCpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through β-catenin/T-cell factor-independent mechanisms.
- Subjects
CANCER invasiveness; CARCINOGENESIS; CANCER research; CELL lines
- Publication
Carcinogenesis, 2007, Vol 28, Issue 12, p2459
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgm178