Zhu Huanzhang, Wang Yun, Chen Jianquan, Cheng Guoxiang, Xue Jinglun
State Key Laboratory of Genetic Engineering, Institute of Genetic, School of Life Sciences, Fudan University, Shanghai 200433, China.
Exp Mol Pathol. 2004 Feb;76(1):44-50. doi: 10.1016/j.yexmp.2003.09.001.
The hepatitis B virus X (HBx) protein is thought to be implicated in the development of human hepatocellular carcinoma (HCC), but its exact function remains controversial. To investigate whether the expression of the HBx gene alone can induce HCC on an inbred C57BL/6 strain that displays a lower spontaneous rate of liver cancer, and to determine if HBx transgenic mice are more susceptible to the effects of hepatocarcinogens, C57-TgN (HBx) X transgenic mice were bred with normal C57BL/6 mice strain. The F1 mice (about 50% HBx positive and 50% HBx negative) were treated with a single dose of diethylnitrosamine (DEN) at 7 days of age, or were untreated. Mice were killed at appropriate time points and were analyzed for histological change in the liver. The expression of HBx protein were examined by using immunohistochemical staining. Glycogen storage foci were examined by using periodic acid-Schiff (PAS) staining. In HBx transgenic mice untreated with DEN, HBx expression and glycogen storage foci were always observed in the liver after 8 weeks, but not obvious histological pathologic changes. Histological examination of liver tissue confirmed that DEN-treated HBx mice developed approximately twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Hepatocellular adenomas and carcinomas were also more frequent in DEN-treated HBx-positive than HBx-negative mice. Taken together, our results suggest that HBx gene expression alone is not sufficient for carcinogenesis, but may act as a promoter for malignant transformation.
乙型肝炎病毒X（HBx）蛋白被认为与人类肝细胞癌（HCC）的发生有关，但其确切功能仍存在争议。为了研究单独的HBx基因表达是否能在肝癌自发率较低的近交C57BL/6品系小鼠中诱发肝癌，并确定HBx转基因小鼠是否对致癌物的作用更敏感，将C57-TgN（HBx）X转基因小鼠与正常C57BL/6小鼠品系进行杂交。F1代小鼠（约50%为HBx阳性，50%为HBx阴性）在7日龄时接受单剂量二乙基亚硝胺（DEN）处理，或不进行处理。在适当的时间点处死小鼠，并对肝脏进行组织学变化分析。采用免疫组织化学染色检测HBx蛋白的表达。采用过碘酸希夫（PAS）染色检测糖原储存灶。在未用DEN处理的HBx转基因小鼠中，8周后肝脏中始终可观察到HBx表达和糖原储存灶，但无明显的组织病理学变化。肝组织的组织学检查证实，经DEN处理的HBx小鼠发生嗜碱性肝细胞局灶性病变的数量约为经处理的野生型同窝小鼠的两倍。在经DEN处理的小鼠中，HBx阳性小鼠发生肝细胞腺瘤和癌的频率也高于HBx阴性小鼠。综上所述，我们的结果表明，单独的HBx基因表达不足以引发癌变，但可能作为恶性转化的促进因子。
