Concurrent Hypermethylation ofSFRP2andDKK2Activates the Wnt/β-Catenin Pathway and Is Associated with Poor Prognosis in Patients with Gastric Cancer.
Aberrant hypermethylation of Wnt antagonists has been observed in gastric cancer. A number of studies have focused on the hypermethylation of a single Wnt antagonist and its role in regulating the activation of signaling. However, how the Wnt antagonists interacted to regulate the signaling pathway has not been reported. In the present study, we systematically investigated the methylation of some Wnt antagonist genes (SFRP2,SFRP4,SFRP5,DKK1,DKK2, andAPC) and their regulatory role in carcinogenesis. We found that aberrant promoter methylation ofSFRP2,SFRP4,DKK1, andDKK2was significantly increased in gastric cancer. Moreover, concurrent hypermethylation ofSFRP2andDKK2was observed in gastric cancer and this was significantly associated with increased expression of β-catenin, indicating that the joint inactivation of these two genes promoted the activation of the Wnt signaling pathway. Further analysis using a multivariate Cox proportional hazards model showed thatDKK2methylation was an independent prognostic factor for poor overall survival, and the predictive value was markedly enhanced when the combined methylation status ofSFRP2andDKK2was considered. In addition, the methylation level ofSFRP4andDKK2was correlated with the patient's age and tumor differentiation, respectively. In conclusion, epigenetic silencing of Wnt antagonists was associated with gastric carcinogenesis, and concurrent hypermethylation ofSFRP2andDKK2could be a potential marker for a prognosis of poor overall survival.
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Hao
H
Wang
Second Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.|Department of General Surgery, The First Hospital of Yulin, Yulin, Shaanxi, China.
Xiang-Long
XL
Duan
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Xiao-Li
XL
Qi
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.|Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi, China.
Lei
L
Meng
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Yi-Song
YS
Xu
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Tong
T
Wu
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Peng-Gao
PG
Dai
D019175:DNA Methylation; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C498622:DKK2 protein, human; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins
DNA methylation; Wnt antagonists; gastric cancer; prognosis; β-catenin