title: The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival.
abstract: The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers. This is frequently related to the methylation of several antagonists of this pathway. This study aimed at the assessment of the profile of methylation of Wnt pathway antagonists and the determination of the prognostic value of the methylation of selected genes in oral carcinomas. The methylation of DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1 was analyzed in 16 oral squamous cell carcinoma cell lines using the methylation-specific polymerase chain reaction. The methylation of selected genes was further analyzed in tumor sections from 43 primary oral carcinoma patients. The analysis of oral carcinoma cell lines showed very frequent methylation of SFRP2 and WIF-1 and also a less frequent methylation of DACH1 and DKK1. On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines. The biallelic methylation of DKK1 correlated with the low level of expression of this gene. Further evaluation of the methylation of DACH1, DKK1, and WIF1 in a clinical patient group confirmed the frequent methylation of WIF1 and intermediate or low frequency of methylation of DACH1 or DKK1, respectively. Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients. Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas. The methylation of WIF1 may be considered a prognostic marker in oral cancers.
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznań University of Medical Sciences, ul. Święcickiego 4, 60-781, Poznań, Poland, paluszcz@ump.edu.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Paluszczak
authors.forename: Joanna
authors.initials: J
authors.lastname: Sarbak
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kostrzewska-Poczekaj
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kiwerska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Jarmuż-Szymczak
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.forename: Daniela
authors.initials: D
authors.lastname: Mielcarek-Kuchta
authors.forename: Wanda
authors.initials: W
authors.lastname: Baer-Dubowska
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486747:DACH1 protein, human; C501126:DKK1 protein, human; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C485569:WIF1 protein, human