Carcinogenesis Advance Access originally published online on August 3, 2007
Carcinogenesis 2007 28(12):2459-2466; doi:10.1093/carcin/bgm178
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Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors
1 First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan
2 Department of Public Health
3 Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8556, Japan
4 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
5 President, Sapporo Medical University, Sapporo 060-8556
* To whom correspondence should be addressed. Tel: +81 11 611 2111 ext. 3211; Fax: +81 11 611 2282; Email: hsuzuki{at}sapmed.ac.jp Correspondence may also be addressed to M. Toyota. Tel: +81 11 211 2111 ext. 3211; Fax: +81 11 611 2282; Email: mtoyota{at}sapmed.ac.jp
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 5' CpG 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.
Abbreviations: CRC, colorectal cancer; DKK, DICKKOPF; Dkk, Dickkopf; GC, gastric cancer; HCC, hepatocellular carcinoma; Lrp, lipoprotein receptor-related protein; MSP, methylation-specific polymerase chain reaction; PCR, polymerase chain reaction; RT, reverse transcriptase; SFRP, secreted frizzled-related protein; TCF, T-cell factor; WIF1, Wnt inhibitory factor 1; 5-aza-dC, 5-aza-2'-deoxycytidine
These authors contributed equally to this work. Received March 25, 2007; revised July 20, 2007; accepted July 25, 2007.
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