Clinical significance of increased expression of Nijmegen breakage syndrome gene (NBS1) in human primary liver cancer.

Abstract

As a DNA repair-associated gene essential for maintaining genomic instability, Nijmegen breakage syndrome gene (NBS1), codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. The aim of this study is to investigate the molecular alteration of Nbs1 in human primary liver cancer, including HBV-associated hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The expression levels of Nbs1 in 110 cases of primary liver cancer, including 85 HCCs and 25 ICCs, were detected by immunohistochemistry, real-time RT-PCR and Western blot analysis. The percentage of Ki-67 antigen-positive cells and the level of phosphorylated histone H2AX (γ-H2AX) were detected to evaluate the relationship of Nbs1 expression with proliferation and the degree of DNA damage in HCC cells. Increased Nbs1 expression was observed in tumor compared to corresponding adjacent non-tumor tissue in 54.6 and 47.3% of HCC cases detected with frozen tissues and paraffin sections. Higher frequency of increased Nbs1 expression was shown in poorly differentiated HCCs (p=0.0265) and in all poorly differentiated ICCs, indicating the increased Nbs1 expression is associated with the degree of malignancy of HCC cells. Moreover, the percentage of Ki-67-positive cells and the level of γ-H2AX correlate well with increased Nbs1 expression in HCC cases, suggesting an activated DNA damage response in proliferating HCC cells with increased Nbs1 expression. Increased Nbs1 expression might play a significant role in liver cancer progression, and the status of Nbs1 expression might be helpful for evaluation of the degree of malignancy of primary liver cancer.