Viral mutations and host diversities that contribute to hepatocarcinogenesis

肝炎病毒感染的自然史包括慢性肝炎、肝硬化和肝细胞癌（HCC）。然而，影响疾病进展为HCC的因素尚未得到很好的阐明。在这里，我们研究了导致肝癌发生的病毒突变和宿主疾病。1)从1.000例获得书面知情同意书的13/C型肝炎患者血清中提取白细胞DNA，并建立包含这些患者临床资料的数据库。然后，我们建立的方法匿名500例患者的WBC DNA样本。2)通过对有无HOC患者的B型肝炎病毒（HBV）X基因核苷酸序列分析，发现HBx基因第38位密码子的氨基酸替换与HOC的发生密切相关。3)干扰素生物学应答者（BR）与干扰素非应答者（NR）相比，HCV核心C端疏水区氨基酸发生变化的频率更高。激活 ...更多信息 与NR组相比，BR组中干扰素治疗后核心蛋白介导的白细胞介素（IL）-8启动子的表达显著降低。HCV核心区氨基酸序列的差异可能通过调节HCV感染患者中IK-8的诱导而与肝炎活动性相关。4)测定HCV核心蛋白、HBx蛋白和丁型肝炎病毒大抗原对细胞内信号传导途径的影响。5)研究了280例日本慢性HCV感染患者（122例HCC）的尿苷5 '-二磷酸葡萄糖醛酸转移酶1A 7（UGT 1A 7）和1 L-1β的遗传多态性。HOC患者UCT 1A 7低活性等位基因（L）/L和高活性等位基因（H）/L的比例（分别为25%和45%）高于非HOC患者（分别为15%和39%），与UGT 1A 7 H/H相比，比值比分别为2.7和1.8。与C/C基因型相比，IL-1β/-31 T/T基因型与HOC的存在显著相关，比值比为2.9。6)为寻找HOC易感基因的单核苷酸多态性（SNPs），对376例日本慢性HCV感染患者（包括170例HOC患者）的172个候选基因的394个SNPs进行了检测。来自三个基因的三个SNP与HOC显著相关。这些SNPs和单倍型将被用作标记，以确定在日本慢性HCV感染患者中HOC风险较高的亚组。少

The natural history of hepatitis virus infection consists of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, the factors influencing disease progression to HCC have not been well elucidated. Here, we studied viral mutations and host diversities that contribute to hepatocarcinogenesis. 1) WBC DNAs were extracted from sera of 1.000 patients with hepatitis 13/C after obtaining written informed consent, and data base containing clinical data of these patients were constructed. Then, WBC DNA samples of 500 patients were anonymized by the method we established. 2) By analyzing hepatitis B virus (HBV) X gene nucleotide sequence in patients with/without HOC, it was revealed that amino acid substitution in codon 38 in HBx is significantly related with HOC. 3) Amino acid changes in C-terminal hydrophobic region of hepatitis C virus (HCV) core were observed more frequently in the interferon biological responders (BR) compared to interferon noivresponders (NR). Activatio … More n of Interleukin (IL)-8 promoter by core proteins significantly decreased after interferon therapy in the BR group compared to the NR group. Differences in amino acid sequence of HCV core possibly correlate with hepatitis activity by modulating IK-8 induction in HCV infected patients. 4) The effect of HCV core protein, HBx protein, and hepatitis delta virus large antigen on intracellular signaling pathway was determined. 5) Genetic polymorphsims of uidine 5'-diphosphate-glucuronosyltransferase 1A7 (UGT 1A7) and 1L-1β were investigated in 280 Japanese patients (122 with HCC) with chronic HCV infections. The proportions of UCT1A7 low activity allele (L)/L and high activity allel (H)/L in patients with HOC (25% and 45%, respectively) were higher than those in patients without HOC (15% and 39%, respectively) with an odds ratio of 2.7 and 1.8, respectively, comared with the UGT1A7 H/H. The IL-1β/-31 T/T genotype showed a significant association with the presence of HOC compared with the C/C genotype with an odds ratio of 2.9. 6) To search of single nucleotide polymorphisms(SNPs) for HOC susceptibility genes, 394 SNPs derived from 172 candidate genes were examined in 376 Japanese patients (including 170patients with HOC) with chronic HCV infection. Three SNPs derived from three genes were significantly associated with HOC. These SNPs and haplotypes will be used as markers to identify a subgroup at higher risk of HOC in Japanese patients with chronic HCV infection. Less