Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors

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 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 beta-catenin/T-cell factor-independent mechanisms.

The Dickkopf‐homolog 3 is expressed in tumor endothelial cells and supports capillary formation

“…Immortalization and malignant transformation are responsible for dedifferentiation of epithelial cells and might induce loss of expression due to methylation of the Dkk-3 promotor, as shown for all dickkopf genes in colorectal cancer. 28 In our IHC analysis of several cancer types we were not able to find any tumor cells expressing Dkk-3.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…In particular, alterations of Dkk expression have been observed in a number of cancer models, which is not surprising given the importance of Wnt signaling in cancer biology. In colon cancer, for example, the observed epigenetic silencing of Dkk1 and other Dkk family genes is likely to contribute further to the activation of the Wnt/bcatenin pathway (Aguilera et al 2006;Sato et al 2007). Dkk1 expression itself can be directly upregulated by Wnt/b-catenin signaling in a T-cell factor (TCF)-dependent manner, but this mechanism appears to be lost through silencing in colon cancer (Gonzalez-Sancho et al 2005).…”

HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

“…(17) Dysregulation of the Wnt signaling pathway has been implicated in gastric carcinogenesis and metastasis. (22,23,(31)(32)(33) Therefore, in the present study, we first assessed the expression profile of Wnt pathway genes in AGS and MKN28 cells. As shown in Figure 3(a), the expression of several Wnt ligands was elevated in both cell lines (i.e.…”