Correlative Analysis of DNA Methyltransferase Expression and Promoter Hypermethylation of Tumor Suppressor Genes in Hepatocellular Carcinoma

Cancer Genomics - Proteomics

ANDREW CHAN¹  NATHALIE WONG²  TAI-WAI LAM²  JOANNA H.-M. TONG²  PAUL B.-S. LAI³  CHOONG-TSEK LIEW²  KA-FAI TO² 

[1] iotechnology and Development Versitech Ltd., The University of Hong Kong, Pokfulam Road, SAR Hong Kong, Chinaiotechnology and Development Versitech Ltd., The University of Hong Kong, Pokfulam Road, SAR Hong Kong, Chinaiotechnology and Development Versitech Ltd., The University of Hong Kong, Pokfulam Road, SAR Hong Kong, China;epartment of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kongepartment of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kongepartment of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kong;epartment of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kongepartment of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kongepartment of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., SAR Hong Kong

关键词: Hepatocellular carcinoma;    promoter hypermethylation;    DNA methyltransferases;    tumor suppressor genes;   

DOI  :  

来源: Delinasios GJ CO

【 摘 要 】

Background: Promoter hypermethylation of tumor suppressor genes (TSGs) is a common phenomenon in liver carcinogenesis, although the controlling mechanism remains unclear. Materials and Methods: The mRNA expression of DNA methyltransferases (DNMT1, 2, 3a, 3b and splice variants 3b3 and 3b4) and methyl-CpG binding protein (MBD2) were quantitated in 51 liver specimens (41 hepatocellular carcinoma (HCC), 1 cholangiocarcinoma, 1 macroregenerative nodule and 8 HCC cell lines) and the expression levels were correlated with the promoter methylation status of 14 TSG, including APC, RASSF1A, SOCS-1, GSTP1, E-cadherin, p14, p15, p16, DAP-kinase, HIC1, MGMT, TIMP-3, hMLH1 and HLTF. Results: Up-regulations of DNMT1, DNMT2, DNMT3a, DNMT3b4 and MBD2 were suggested in more than 40% of the cases. In particular, the overexpression of DNMT3b and the splice variant DNMT3b3 were identified in as many as 91% and 97.8% of cases, respectively. Using methylation-specific PCR, the most frequently methylated TSGs were APC (90.2%), RASSF1A (86.3%), SOC-1 (74.5%), GSTP1 (72.5%), E-cadherin (64.7%) and p16 (58%). Statistical correlations did not suggest the DNMTs and MBD2 expressions in association with cumulative methylated index in individual cases, but increased expression levels of DNMT2 and DNMT3a showed significant association with the hypermethylation of GSTP1 (p=0.014) and DAP-kinase (p=0.006), respectively. Furthermore, the analysis with clinicopathological data indicated aberrant DAP-kinase methylation was significantly associated with advanced stage T3/T4 HCC tumors (p=0.032) and that p16 hypermethylation was distinct more prevalent in tumors arising from a cirrhotic background (p=0.005). Conclusion: Our study indicated that DNMT deregulations are common in liver cancers and the existence of a relationship between DNMT2 and DNMT3a overexpression and promoter hypermethylation of candidate tumor suppressor genes in HCC.

【 授权许可】

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