Apoptosis of Hepatitis B Virus-expressing Liver Tumor Cells Induced by a High Concentration of Nucleos(t)ide Analogue.

Abstract

We investigated the expression of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and HBV X protein (HBx) in human hepatocellular carcinoma (HCC) and evaluated the effect of high-concentration nucleos(t)ide analogs (NUCs) on liver tumor cell lines. This study consisted of three parts: part I used human blood and non-tumor liver tissues; part II used human HCC and adjacent liver tissues; and part III used an HBV-expressing liver tumor cell line. There were close correlations among blood and liver HBV DNA and liver cccDNA. HBV cccDNA and HBx were highly up-regulated in HCC compared to adjacent liver tissues despite NUC therapy. HBV cccDNA and HBx were highly up-regulated in the cccDNA-expressing HepG2.2.15 cell line. Their expression was down-regulated and apoptosis was induced by a very high concentration of NUCs in dose- and time-dependent manner. Very high concentrations of NUCs may have a novel potential to kill replicating HBV-expressing liver tumor cells.