Differential MicroRNA Expression Between Hepatitis B and Hepatitis C Leading Disease Progression to Hepatocellular Carcinoma

MicroRNA (miRNA) plays an important role in the pathology of various diseases, including infection and cancer. Using real-time polymerase chain reaction, we measured the expression of 188 miRNAs in liver tissues obtained from 12 patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and 14 patients with hepatitis C virus (HCV)-related HCC, including background liver tissues and normal liver tissues obtained from nine patients. Global gene expression in the same tissues was analyzed via complementary DNA microarray to examine whether the differentially expressed miRNAs could regulate their target genes. Detailed analysis of the differentially expressed miRNA revealed two types of miRNA, one associated with HBV and HCV infections (n = 19), the other with the stage of liver disease (n = 3 1). Pathway analysis of targeted genes using infection-associated miRNAs revealed that the pathways related to cell death, DNA damage, recombination, and signal transduction were activated in HBV-infected liver, and those related to immune response, antigen presentation, cell cycle, proteasome, and lipid metabolism were activated in HCV-infected liver. The differences in the expression of infection-associated miRNAs in the liver correlated significantly with those observed in Huh7.5 cells in which infectious HBV or HCV clones replicated. Out of the 31 miRNAs associated with disease state, 17 were down-regulated in HCC, which up-regulated cancer-associated pathways such as cell cycle, adhesion, proteolysis, transcription, and translation; 6 miRNAs were up-regulated in HCC, which down-regulated anti-tumor immune response. Conclusion: miRNAs are important mediators of HBV and HCV infection as well as liver disease progression, and therefore could be potential therapeutic target molecules. (HEPATOLOGY 2009;49:1098-1112.)