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.

The anti-apoptotic PON2 protein is Wnt/β-catenin-regulated and correlates with radiotherapy resistance in OSCC patients

“…In accordance, Padhi et al reported of a correlation between β-cat expression and poor prognosis in head and neck cancer [12] in vivo . This is supported by the very recent finding that inactivation of several Wnt inhibitors through methylation is frequently found in oral cancer, correlating with a shorter survival [13]. The association of aberrant Wnt signaling to e.g.…”

Decreased expression of SOX7 induces cell proliferation and invasion and correlates with poor prognosis in oral squamous cell carcinoma

“…Dysregulation of the Wnt signaling pathway can promote the progression of oral cancer and is significantly associated with prognosis in patients with OSCC . Epigenetic silencing by DNA methylation of Wnt antagonists is frequently detected in oral cancer and is considered a prognostic marker . Lee et al have showed a significant association between EGFR expression and aberrant accumulation of β‐catenin in oral cancer, suggesting EGFR signaling regulates β‐catenin localization and stability.…”

Rosmarinic Acid Inhibits Cell Growth and Migration in Head and Neck Squamous Cell Carcinoma Cell Lines by Attenuating Epidermal Growth Factor Receptor Signaling

“…Consistent with this finding, we observed inhibition of ERK phosphorylation in HNSCC following treatment with 80 μg/ml RA ( Figure 2C). However, it is important to note that there are a number of signaling pathways, in addition to the MAPK/ERK pathway, that are responsible for cell proliferation and survival in HNSCC, such as Wnt [47] and JAK/STAT [48,49] signaling. Given the relative paucity of information in the literature describing the effects of RA on tumor cell signaling, next steps in our laboratory will focus on elucidating parallel signaling cascades and upstream receptors that might also be targeted by RA in HNSCC.…”