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Influence of hepatitis B virus core promoter mutations on hepatocellular carcinoma among Japanese patients

乙型肝炎病毒核心启动子突变对日本患者肝细胞癌的影响

基本信息

批准号：
18590741
负责人：
TANAKA Yasuhito
金额：
$ 2.41万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590741/
关键词：
Hepatitis B virus (HBV)HBV genotype core promoter Mutation Hepatocellular carcinoma Hepatitis B Viral replication Chimeric mice HBV genotype ウイルス複製

项目摘要

Viral differences in enhancer II/core promoter and precore regions between the subgenotypes and their association with hepatocellular carcinoma (HCC) were assessed in 3 independent studies; 1)a matched cross-sectional control study of 118 carriers with HBV/C1/Cs and 210 HBV/C2/Ce; 2) a control study among 8 IC and 8 HCC patients infected with HBV genotype C before and after seroconversion; 3)an age, sex, and HBeAg status matched cross-sectional control study between 80 Japanese patients infected with HBV/C2 with HCC and 80 without HCC. Our data indicate that T1653 and/or V1753 mutations in addition to T1762/A1764 are strongly associated with HCC in context of HBeAg status among HBV/C-carriers. HBV/C subgenotypes have specific mutation patterns, which is probably responsible for increased carcinogenesis of HBV/C2/Ce.HBV of various genotypes may induce liver disease of distinct severity, but the underlying virological differences are not well defined. Huh7 cells were transfected with plasmids carrying 1.24-fold the HBV genome of different genotypes/subgenotypes (2 strains each for Aa/A1, Ae/A2, Ba/B2 and D; 3 each for Bj/B1 and C). uPA/SCID mice with human hepatocytes were inoculated with mouse passages of virions recovered from culture supernatants. Serum levels of HBV DNA in these mice were higher for C than Ae by 2 logs during 4-7 weeks post-inoculation. In conclusion, virological differences among HBV genotypes were demonstrated both in tissue culture and chimeric mice. These differences may influence HBV infections with distinct genotypes in clinical and epidemiological settings.

3项独立研究评估了亚型间增强子II/核心启动子和前孔区域的病毒差异及其与肝细胞癌（HCC）的关系；1)对118名HBV/C1/Cs携带者和210名HBV/C2/Ce携带者进行匹配的横断面对照研究；2) 8例IC和8例HCC感染HBV基因型患者血清转化前后对照研究；3) 80例日本HBV/C2合并HCC患者和80例非HCC患者的年龄、性别和HBeAg状态匹配的横断面对照研究。我们的数据表明，在HBV/ c携带者的HBeAg状态下，T1653和/或V1753突变以及T1762/A1764与HCC密切相关。HBV/C亚基因型具有特定的突变模式，这可能是导致HBV/C2/Ce癌变增加的原因。不同基因型的HBV可诱发不同严重程度的肝脏疾病，但潜在的病毒学差异尚未明确。将携带1.24倍不同基因型/亚基因型HBV基因组的质粒（Aa/A1、Ae/A2、Ba/B2和D各2株，Bj/B1和C各3株）转染Huh7细胞，用培养上清中回收的病毒粒子小鼠传代接种人肝细胞uPA/SCID小鼠。在接种后4-7周，这些小鼠的血清HBV DNA水平C比Ae高2个logs。总之，在组织培养和嵌合小鼠中，HBV基因型之间存在病毒学差异。这些差异可能影响临床和流行病学背景下不同基因型的HBV感染。