Lee Jong-Han, Han Kwang-Hyub, Lee Jae Myun, Park Jeon Han, Kim Hyon-Suk
Department of Laboratory Medicine, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea.
Clin Vaccine Immunol. 2011 Jun;18(6):914-21. doi: 10.1128/CVI.00474-10. Epub 2011 Apr 13.
The hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131 (double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] = 1.101 to 12.768, P = 0.033) and 5.34-fold (95% CI = 1.65 to 17.309, P = 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-κB activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-κB activity. Other regulatory pathways seem to exist for NF-κB activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-κB activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.
在一项荟萃分析中，乙型肝炎病毒（HBV）前S区突变C1653T、T1753V和A1762T/G1764A被报道为肝细胞癌（HCC）的一个强风险因素。HBV核心启动子部分与HBx编码序列重叠，因此1762和1764位核苷酸突变会导致HBV X蛋白（HBx）的第130和131位氨基酸替换。我们试图阐明HBx突变对HCC发生发展的影响。本研究纳入慢性HBV感染患者：42例慢性乙型肝炎（CHB）患者、23例肝硬化（LC）患者和31例HCC患者。直接测序显示，HBx131、HBx130、HBx5、HBx94和HBx38氨基酸突变在HCC患者中较为常见。在各种突变中，HBx130 + HBx131（双）突变和HBx5 + HBx130 + HBx131（三）突变在HCC患者中显著高发。与CHB患者相比，双突变和三突变使HCC风险分别增加3.75倍（95%置信区间[CI]=1.101至12.768，P = 0.033）和5.34倍（95% CI = 1.65至17.309，P = 0.005）。在功能上，具有HBx5突变体和双突变体的细胞中NF-κB活性水平显著高于野生型细胞和三突变体细胞。三突变并未增加NF-κB活性。似乎存在其他调节途径用于NF-κB激活。总之，特定HBx突变可能通过激活NF-κB活性促进HCC发生发展。C2基因型HBV中的HBx5突变似乎是HCC发生发展的一个风险因素，可用于预测慢性HBV感染患者的临床结局。
