Hepatitis B virus infection in hepatocellular carcinoma tissues upregulates expression of DNA methyltransferases

Purpose: Our previous research identified that Hepatitis B virus (HBV) infection results in the increased methylation of p16; however, the mechanism(s) of the methylation changes observed following HBV infection are yet to be deduced. DNA methylation is governed by the interaction of DNA methyltransferases (DNMT). To investigate the expression of DNMT in cancerous tissue, cirrhotic tissues and non-cancerous tissue, we examined the relationship between HBV infection and DNMT expression.

Methods: We compared the mRNA expression levels of the four DNMTs in cancerous, cirrhotic and matched non-cancerous tissues of HCC with HBV infection by real-time PCR.

Results: The results showed that compared with the level in the corresponding non-cancerous liver tissues, the levels of DNMT1, DNMT3A and DNMT3B were elevated in 54.5%, 68.2% and 38.6% of cancerous tissues and 31.4%, 40% and 25.8% of cirrhotic tissues, respectively. The average mRNA expression for DNMT2 in cancerous and cirrhotic tissues of HCC was not significantly different from that in the corresponding non-cancerous liver tissues. In HBV-associated tissue samples, both the average level and the elevated frequency of DNMT1, DNMT3A and DNMT3B mRNA expression were significantly higher than in non-HBV-associated cirrhotic and cancerous tissues; even in non-cancerous tissues, the mRNA levels of DNMT1 and DNMT3A in HBV-associated samples were significantly higher than in the non-HBV-associated samples. Correlations analysis demonstrated a significant association between HBV infection and the overexpression of DNMTs and p16 methylation.

Conclusions: The results of our current study suggest that persistent HBV infection can stimulate the overexpression of DNMTs, particularly DNMT1, DNMT3A and DNMT3B, which may result in the hyper-methylation/inactivation of p16, thus indirectly regulating the progression of hepatocellular carcinogenesis.