Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer.
BACKGROUND
Abnormal activation of the Wnt/beta-catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk-3 in these cancers and its prognostic significance in gastric cancer.


METHODS
Dkk-3 methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony-formation assay. For survival analyses, the authors used Kaplan-Meier plots, the log-rank test, and Cox proportional regression.


RESULTS
Dkk-3 was silenced or down-regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of Dkk-3 suppressed colony formation. Moreover, methylation of Dkk-3 was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of Dkk-3 methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that Dkk-3 methylation was associated significantly and independently with poor disease survival (relative risk, 2.534; 95% confidence interval, 1.54-4.17; P=.002) in gastric cancer, but not in colorectal cancer. Kaplan-Meier survival curves revealed that patients who had Dkk-3 methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have Dkk-3 methylation (median, 2.68 years; P<.0001; log-rank test).


CONCLUSIONS
Epigenetic silencing of the Dkk-3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients.
Yu
Jun
J
Institute of Digestive Disease, Department of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR. junyu@cuhk.edu.hk
Tao
Qian
Q
Cheng
Yuen Y
YY
Lee
Kwan Y
KY
Ng
Simon S M
SS
Cheung
Kin F
KF
Tian
Linwei
L
Rha
Sun Y
SY
Neumann
Ulf
U
Röcken
Christoph
C
Ebert
Matthias P A
MP
Chan
Francis K L
FK
Sung
Joseph J Y
JJ
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*; D016019:Survival Analysis; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin