International Journal of Medical Sciences

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17 October 2017

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Int J Med Sci 2013; 10(12):1727-1739. doi:10.7150/ijms.6884

Research Paper

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

Goot Heah Khor1,2,3,8✉, Gabriele Ruth Anisah Froemming2, Rosnah Binti Zain3,4, Mannil Thomas Abraham5, Effat Omar2, Su Keng Tan6, Aik Choon Tan7, Vui King Vincent-Chong3, Kwai Lin Thong8,9✉

1. Centre of Studies for Preclinical Science, Faculty of Dentistry, Universiti Teknologi MARA, Shah Alam. Selangor, Malaysia.
2. Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia.
3. Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
4. Department of Oro-maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
5. Tengku Ampuan Rahimah Hospital, Department of Oral and Maxillofacial Surgery, Ministry of Health Malaysia, Malaysia.
6. Oral Maxillofacial Diagnostic and Medicine, Faculty of Dentistry, Universiti Teknologi MARA, Shah Alam. Selangor, Malaysia.
7. Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
8. Laboratory of Biomedical Science and Molecular Microbiology, UMBIO Cluster, Institute of Postgraduate, University of Malaya, Kuala Lumpur, Malaysia.
9. Institute of Biological Science, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.

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.

Keywords: DNA methylation profiling, promoter hypermethylation, Oral Squamous Cell Carcinoma, DDAH2, DUSP1, protein expression.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Khor GH, Froemming GRA, Zain RB, Abraham MT, Omar E, Tan SK, Tan AC, Vincent-Chong VK, Thong KL. DNA Methylation Profiling Revealed Promoter Hypermethylation-induced Silencing of p16, DDAH2 and DUSP1 in Primary Oral Squamous Cell Carcinoma. Int J Med Sci 2013; 10(12):1727-1739. doi:10.7150/ijms.6884. Available from http://www.medsci.org/v10p1727.htm