Putative tumour-suppressor gene DAB2is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma

BMC Cancer

Research Article

Joanna H Tong¹  Raymond W Lung¹  Shuk L Chau¹  Anthony W Chan¹  Ken K So¹  Patrick P Leung¹  David C Ng¹  Kwok W Lo²  Ka F To³  Michael W Chan⁴  Tin L Lee⁵ 

[1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, P.R. China;Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, P.R. China;State Key Laboratory in Oncology in South China, Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, P.R. China;Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, P.R. China;State Key Laboratory in Oncology in South China, Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, P.R. China;Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, P.R. China;Department of Life science, National Chung Cheng University, Min-Hsiung, Taiwan, Chia-Yi, China;The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA;

关键词: Bisulfite Sequencing;    Tumour Suppressor Effect;    DAB2 Gene;    Normal Nasopharyngeal Epithelium;    DAB2 Expression;   

DOI  :  10.1186/1471-2407-10-253

 received in 2009-10-09, accepted in 2010-06-03,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundHuman Disabled-2 (DAB2), is a multi-function signalling molecule that it is frequently down-regulated in human cancers. We aimed to investigate the possible tumour suppressor effect of DAB2 in nasopharyngeal carcinoma (NPC).MethodsWe studied the expression of DAB2 in NPC cell lines, xenografts and primary tumour samples. The status of promoter methylation was assessed by methylation specific PCR and bisulfite sequencing. The functional role of DAB2 in NPC was investigated by re-introducing DAB2 expression into NPC cell line C666-1.ResultsDecrease or absent of DAB2 transcript was observed in NPC cell lines and xenografts. Loss of DAB2 protein expression was seen in 72% (33/46) of primary NPC as demonstrated by immunohistochemistry. Aberrant DAB2 promoter methylation was detected in 65.2% (30/46) of primary NPC samples by methylation specific PCR. Treatment of the DAB2 negative NPC cell line C666-1 with 5-aza-2'-deoxycytidine resulted in restoration of DAB2 expression in a dose-dependent manner. Overexpression of DAB2 in NPC cell line C666-1 resulted in reduced growth rate and 35% reduction in anchorage-dependent colony formation, and inhibition of serum-induced c-Fos expression compared to vector-transfected controls. Over expression of DAB2 resulted in alterations of multiple pathways as demonstrated by expression profiling and functional network analysis, which confirmed the role of DAB2 as an adaptor molecule involved in multiple receptor-mediated signalling pathways.ConclusionsWe report the frequent down regulation of DAB2 in NPC and the promoter hypermethylation contributes to the loss of expression of DAB2. This is the first study demonstrating frequent DAB2 promoter hypermethylation in human cancer. Our functional studies support the putative tumour suppressor effect of DAB2 in NPC cells.

【 授权许可】

CC BY   
© Tong et al; licensee BioMed Central Ltd. 2010