The Oncogenic Potential of Hepatitis B virus rtA181T/ Surface Truncation Mutant
The Oncogenic Potential of Hepatitis B virus rtA181T/ Surface Truncation Mutant
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DOI：
10.1177/135965350801300701
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发表时间：
2008-10
影响因子：
1.2
通讯作者：
M. Lai;C. Yeh
中科院分区：
文献类型：
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作者：
M. Lai;C. Yeh
背景此前，在台湾患者中发现了一种不太普遍的拉米夫定耐药突变体（rtA 181 T），其中表面基因中同时出现终止密码子，导致乙型肝炎病毒（B）表面抗原分泌受损。rtA 181 T突变体也赋予阿德福韦酯耐药性。我们发现了一个39岁的晚期肝细胞癌患者，谁是血清阳性的HBV e抗原，但血清阴性的HBV表面抗原。核苷酸序列分析显示，聚合酶rtA 181 T/表面截短突变体的存在下，在血清和肝癌样品。令人惊讶的是，这名患者从未接受过拉米夫定或阿德福韦抗病毒治疗。在这里，我们的目的是评估HBV rtA 181 T/表面截短突变体的致癌潜力。方法采用定点突变和反式激活实验，分别对c-Myc、c-Fos和猿猴病毒40启动子的前S/S截短突变体的反式激活活性进行评价。用稳定表达突变体的NIH 3 T3细胞在裸鼠体内评价致瘤性。结果反式激活实验表明，相应的pre-S/S截短突变体能够反式激活猿猴病毒40和人c-Myc启动子，但不能反式激活c-Fos启动子。稳定表达该突变体的NIH 3 T3细胞在5只裸鼠中的4只中具有致瘤性。结论HBV聚合酶rtA 181 T/表面截短突变体在未经抗病毒治疗的情况下可自发出现。这种突变体在晚期肝细胞癌患者中的存在及其致癌潜力值得仔细重新评估目前延长抗病毒治疗的策略。
Background Previously, a less prevalent lamivudine-resistant mutant (rtA181T) was discovered in Taiwanese patients, in which a stop codon in the surface gene concomitantly occurred, leading to impaired secretion of hepatitis B virus (HBV) surface antigen. The rtA181T mutant also conferred drug resistance to adefovir. We discovered a 39-year-old patient with advanced hepatocellular carcionoma, who was seropositive for HBV e antigen but seronegative for HBV surface antigen. Nucleotide sequence analysis revealed the presence of polymerase rtA181T/surface truncation mutant in both the serum and hepatoma samples. Surprisingly, this patient has never received lamivudine or adefovir antiviral therapy. Here, we aimed to evaluate the oncogenic potential of HBV rtA181T/surface truncation mutant. Methods Site-directed mutagenesis experiments followed by transactivation assays were performed in HepG2 cells to evaluate the transactivation activities of the corresponding pre-S/S truncation mutant for c-Myc, c-Fos and Simian virus 40 promoters. NIH3T3 cells stably expressing the mutant were used to assess the tumourigenicity in nude mice. Results Transactivation experiments revealed that the corresponding pre-S/S truncation mutant was capable of transactivating the Simian virus 40 and human c-Myc promoters but not the c-Fos promoter. NIH3T3 cells stably expressing this mutant were tumourigenic in four of the five nude mice tested. Conclusion Our data indicate that an HBV polymerase rtA181T/surface truncation mutant could emerge spontaneously without previous antiviral treatment. The presence of this mutant in a patient with advanced hepatocellular carcinoma as well as its oncogenic potential warrants careful re-evaluation of the current strategy of prolonged antiviral therapy.