Su Ih-Jen, Wang Hui-Ching, Wu Han-Chieh, Huang Wen-Ya
Division of Clinical Research, National Health Research Institutes, Tainan, Taiwan.
J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1169-74. doi: 10.1111/j.1440-1746.2008.05348.x. Epub 2008 May 26.
The discovery of "ground glass" hepatocytes (GGH) that contain hepatitis B virus (HBV) surface antigens by Hadziyannis and Popper in 1973 represents a historical landmark in the pathology of chronic HBV infection. Different types of GGH have been correlated to the expression patterns of surface/core antigens and the stages of virus replication. The original two types (designated types I & II) of GGH were found to contain specific pre-S mutants with deletions over either pre-S1 or pre-S2 regions, respectively. Type II GGH consistently harbor pre-S2 deletion mutants, which can escape from immune attack and grow preferentially to form clusters. Both types of pre-S mutants can induce endoplasmic reticulum (ER) stress and oxidative DNA damage. The pre-S2 mutants, albeit inducing a weaker level of ER stress signals, could additionally initiate ER stress-independent retinoblastoma/adenovirus E2 promoter binding factor/cyclin A signaling through their interaction with c-Jun activation domain binding protein 1 to degrade p27, illustrating the growth advantage of type II GGH. The combined effects of genomic instability and the proliferation of hepatocytes harboring pre-S mutants could potentially lead to hepatocarcinogenesis over the decades of chronic HBV infection. The presence of pre-S mutants in sera was reported to carry a high risk of developing hepatocellular carcinoma (HCC). Furthermore, transgenic mice harboring pre-S2 mutant plasmids have been shown to develop a dysplastic change of hepatocytes and HCC. Therefore, in addition to being a histological marker of chronic HBV infection, GGH, particularly type II GGH, may represent the preneoplastic lesions of HBV-related HCC.
1973年，哈齐亚尼斯和波珀发现含有乙型肝炎病毒（HBV）表面抗原的“毛玻璃”样肝细胞（GGH），这是慢性HBV感染病理学中的一个历史里程碑。不同类型的GGH与表面/核心抗原的表达模式及病毒复制阶段相关。最初发现的两种类型（分别命名为I型和II型）GGH，被发现分别含有在pre-S1或pre-S2区域有缺失的特定pre-S突变体。II型GGH始终携带pre-S2缺失突变体，其能够逃避免疫攻击并优先生长形成簇。两种类型的pre-S突变体均可诱导内质网（ER）应激和氧化性DNA损伤。pre-S2突变体虽然诱导的ER应激信号水平较弱，但可通过与c-Jun激活域结合蛋白1相互作用降解p27，额外启动不依赖ER应激的视网膜母细胞瘤/腺病毒E2启动子结合因子/细胞周期蛋白A信号通路，这说明了II型GGH的生长优势。在数十年的慢性HBV感染过程中，基因组不稳定以及携带pre-S突变体的肝细胞增殖的综合作用可能会导致肝癌发生。据报道，血清中存在pre-S突变体具有发生肝细胞癌（HCC）的高风险。此外，携带pre-S2突变体质粒的转基因小鼠已被证明会发生肝细胞发育异常变化和HCC。因此，GGH，尤其是II型GGH，除了作为慢性HBV感染的组织学标志物外，可能还代表了HBV相关HCC的癌前病变。
