DNA Methylation Profiling Revealed Promoter Hypermethylation-induced Silencing of p16, DDAH2 and DUSP1 in Primary Oral Squamous Cell Carcinoma

Abstract

Background: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC.Methods: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study.Results: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially-hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference.Conclusions: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future.

DUSP1 Phosphatase Regulates the Proinflammatory Milieu in Head and Neck Squamous Cell Carcinoma

“…Genomic studies have not identified a common mutation or deletion, but a recent DNA methylation screen identified significantly increased promoter hypermethylation in over 80% of oral cancer tissues (18). Pharmaceutical intervention to induce DUSP1 expression, with rosiglitazone and mapracorat, are currently being explored in vitro with promising results (19,20).…”

Screening of Differential Promoter Hypermethylated Genes in Primary Oral Squamous Cell Carcinoma

“…Only selected differentially hypermethylated probes in OSCC patients that passed the filtration criteria were then subjected to Partek Genomics Suite 6.5 analysis (Partek Inc., USA) for gene selection. DOI:http://dx.doi.org/10.7314/APJCP.2014.15.20.8957 Promoter Hypermethylated Genes in Primary Oral Squamous Cell Carcinoma of TP73, PIK3R5, and CELSR3 were selected from the gene list based on the selection criteria form our previous experiment (Khor et al, 2013).…”

CMTM3 inhibits cell growth and migration and predicts favorable survival in oral squamous cell carcinoma

“…Analyses carried out on DNA methylation patterns show that this process can be used as a biomarker for early diagnosis as well as for classification, prognosis, and therapy of human cancers [6]. Previous studies have identified the methylation of the promoter regions of over 40 tumor suppressor genes in oral squamous cell carcinoma and precancerous lesions, such as CDKN2A, MGMT, DAPK1, RUNX3, and p14 ARF [7][8][9][10][11][12][13].…”