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

Khor, Goot Heah and Froemming, Gabriele Ruth Anisah and Zain, R.B. and Abraham, Mannil Thomas and Omar, Effat and Tan, Su Keng and Tan, Aik Choon and Chong, Vincent Vui King and Thong, Kwai Lin (2013) DNA Methylation Profiling Revealed Promoter Hypermethylation-induced Silencing of p16, DDAH2 and DUSP1 in Primary Oral Squamous Cell Carcinoma. International Journal of Medical Sciences, 10 (12). pp. 1727-1739. ISSN 1449-1907, DOI https://doi.org/10.7150/ijms.6884.

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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.

Item Type: Article
Funders: PPP Grant (PV046-2011) of University of Malaya, Malaysia, Research Intensive Faculty (600-RMI/DANA 5/3/RIF (633/2012)) grant of Universiti Teknologi MARA, Malaysia, Science fund grant of Ministry of Science, Technology and innovation (MOSTI), Malaysia, Fundamental Research Grant Scheme (FRGS) of the Ministry of Higher Education, Malaysia
Uncontrolled Keywords: DNA methylation profiling; promoter hypermethylation; Oral Squamous Cell Carcinoma; DDAH2; DUSP1; protein expression
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history
R Medicine > RK Dentistry
Divisions: Faculty of Dentistry
Faculty of Science > Institute of Biological Sciences
Depositing User: Prof. Dr Kwai Lin Thong
Date Deposited: 25 Jun 2014 06:57
Last Modified: 20 Nov 2019 01:17
URI: http://eprints.um.edu.my/id/eprint/10644

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