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.
Highlights
Oral and oropharyngeal squamous cell carcinoma (OSCC) is a common cancer of the head and neck region, and it ranks as the eighth most prevalent cancer among males in the USA [1]
When the pathway is in the resting state, the chief protein that serves for signal transduction–β-catenin is phosphorylated by an inhibitory complex which comprises of glycogen synthase kinase 3β (GSK-3β), casein kinase 1α, adenomatous polyposis coli (APC), and Axin
The aim of the present study was to assess the frequency of gene promoter methylation of Wnt pathway antagonists (DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1) in oropharyngeal squamous cell carcinoma cell lines and establish the diagnostic potential of the most promising genes in respect to correlation with important clinicopathologic data such as tumor recurrence or disease-free survival in a group of oropharyngeal cancer patients
Summary
Oral and oropharyngeal squamous cell carcinoma (OSCC) is a common cancer of the head and neck region, and it ranks as the eighth most prevalent cancer among males in the USA [1]. The overall 5-year survival rates are around 50–60 %, and despite the growing understanding of the molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC), therapy outcomes remain unaltered what is explained by a relatively frequent rate of tumor relapse or the appearance of metastases [2]. The binding of Wnt ligands to Frizzled receptors activates Dishevelled, which inhibits the activity of GSK-3β and blocks the degradation of β-catenin This enables the accumulation of β-catenin in the cytoplasm and its subsequent translocation to the nucleus where it binds the TCF/LEF family of transcription factors and stimulates the expression of genes which enhance cell cycle and cell migration, such as CCND1, MYC, MMP-7, or survivin [4]
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