Genome-wide screen for hepermethylated genes in hepatocellular carcinoma

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Gene silencing due to aberrant DNA methylation causes inactivation of tumor suppressor genes, which plays an important role during carcinogenesis. Expression of p16INK4a gene was suppressed due to aberrant DNA methylation in hepatocellular carcinoma and other novel genes could be suppressed by the same mechanism. Therefore, we analyzed gene expression profile altered after DNA methyltransferase inhibitor, 5-aza-2' deoxycytidine (5Aza-dC) treatment using cDNA microarray in 6 hepatome cell lines. Among 14 genes exhibiting the substantial induction (more than 5-fold changes) after 5Aza-dC treatment in multiple hepatoma cell lines, based on cDNA microarray analysis, 6 genes including hepatocyte growth factor activator inhibitor 2 (HAI2), E-cadherin, collagen type 1 alpha 2 (COL1A2), insulin-like growth factor binding protein 2 (IGFBP2), connective tissue growth factor (CTGF) and fibronectin 1 (FN1) exhibited hypermethylation of CpG islands on hepatoma cells. In further studies of primary hepatoma tissues using methylation-specific PCR (MS-PCR), hypermethylation of HAI2 was detected in tumorous tissues more often than in corresponding nontumorous tissues. In conclusion, we could identify 6 hypermethylated genes in hepatoma by microarray based strategy. Aberrant methylation of HAI2 gene might be involved in hepatocarcinogenesis due to overexpression of hepatocyte growth factor.