Kim Y C, Song K S, Yoon G, Nam M J, Ryu W S
Department of Biochemistry, Yonsei University, 134 Shinchondong, Seodaemungu, Seoul, Korea 120-749.
Oncogene. 2001 Jan 4;20(1):16-23. doi: 10.1038/sj.onc.1203840.
The hepatitis B virus HBx protein is a promiscuous transactivator implicated in the development of hepatocellular carcinoma. The ectopic expression of HBx fails to transform both primary and immortalized rodent cells, but rather induces apoptosis. Furthermore, most transgenic mice harboring HBx do not develop liver tumors. Thus, it remains unclear whether and how HBx contributes to oncogenesis. Here, we show that HBx collaborates with activated H-ras to transform immortalized rodent cells. Indeed, REF52 cells transfected by both HBx and activated H-ras were morphologically transformed and were able to grow in soft agar. Remarkably, nude mice injected with REF52 cells transfected by both HBx and activated H-ras developed tumors, whereas the mice injected with REF52 cells transfected by either gene alone did not. Thus, we concluded that HBx could contribute to neoplastic transformation of cells in collaboration with other oncogenes, such as H-ras, that renders cells to overcome the HBx-mediated apoptosis. Further, we found that HBx mediated apoptosis was suppressed by activated H-ras through activation of the phosphatidylinositol-3 kinase and Akt pathway. Data presented here firmly established the oncogenic potential of HBx during multistage carcinogenesis. Oncogene (2001) 20, 16 - 23.
乙肝病毒X蛋白（HBx）是一种具有多种作用的反式激活因子，与肝细胞癌的发生发展有关。HBx的异位表达无法使原代和永生化啮齿动物细胞发生转化，反而会诱导细胞凋亡。此外，大多数携带HBx的转基因小鼠并不会发生肝肿瘤。因此，HBx是否以及如何促进肿瘤发生仍不清楚。在此，我们发现HBx与激活的H-ras协同作用可使永生化啮齿动物细胞发生转化。事实上，同时转染了HBx和激活的H-ras的REF52细胞在形态上发生了转化，并且能够在软琼脂中生长。值得注意的是，注射了同时转染了HBx和激活的H-ras的REF52细胞的裸鼠发生了肿瘤，而注射了单独转染任一基因的REF52细胞的小鼠则未发生肿瘤。因此，我们得出结论：HBx可与其他癌基因（如H-ras）协同作用，促进细胞的肿瘤性转化，使细胞克服HBx介导的细胞凋亡。此外，我们发现激活的H-ras通过激活磷脂酰肌醇-3激酶和Akt途径抑制了HBx介导的细胞凋亡。本文提供的数据有力地证实了HBx在多阶段致癌过程中的致癌潜力。《癌基因》（2001年）第20卷，第16 - 23页
