Pu Peiyu, Kang Chunsheng, Li Jie, Jiang Hao, Cheng Jinquan
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, People's Republic of China,
J Neurooncol. 2006 Jan;76(1):1-11. doi: 10.1007/s11060-005-3029-3.
The oncogenic role of AKT2 in the development of malignant gliomas was examined by using antisense approach. AKT2 expression was significantly inhibited in rat C6 glioma cells transfected with antisense AKT2 cDNA construct (LXSN-AS-AKT2). In addition, the transfected cells proliferated at a lowered level and apoptosis was induced. For in vivo studies, parental C6 cells and C6 cells transfected with LXSN-AS-AKT2 were implanted stereotactically into the right caudate nucleus of SD rats (control C6 group and transfected group). The rats bearing well-established C6 gliomas were treated with LXSN-AS-AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group). The mean survival of the rats of control C6 group and treated control group was 17.8+/-0.92 days and 17.5+/-1.10 days, respectively. The mean survival of the rats of transfected and treated group was significantly prolonged. MR images revealed distinct cerebral tumor foci in all of the control rats, whereas four rats in transfected group did not develop tumors and the tumor foci in five rats of treated group were regressed and disappeared. The expression of AKT2, PCNA, MMP2/9, and cyclin D were inhibited in the tumors of rats in transfected and treated groups while GFAP expression was increased. These results suggest that AKT pathway may play an important role in the development and progression of gliomas. Anti-AKT approach will open a new perspective for a targeted molecular therapy of malignant gliomas.
采用反义技术研究了AKT2在恶性胶质瘤发生中的致癌作用。用反义AKT2 cDNA构建体（LXSN-AS-AKT2）转染大鼠C6胶质瘤细胞后，AKT2表达显著受到抑制。此外，转染后的细胞增殖水平降低，并诱导了细胞凋亡。在体内研究中，将亲代C6细胞和转染了LXSN-AS-AKT2的C6细胞立体定向植入SD大鼠的右侧尾状核（对照组C6组和转染组）。对已形成C6胶质瘤的大鼠进行瘤内注射LXSN-AS-AKT2 DNA或LXSN（空载体）-脂质体复合物处理（处理组和对照处理组）。对照组C6组和对照处理组大鼠的平均生存期分别为17.8±0.92天和17.5±1.10天。转染并处理组大鼠的平均生存期显著延长。磁共振成像显示所有对照大鼠均有明显的脑肿瘤灶，而转染组有4只大鼠未发生肿瘤，处理组有5只大鼠的肿瘤灶消退并消失。转染并处理组大鼠肿瘤中AKT2、PCNA、MMP2/9和细胞周期蛋白D的表达受到抑制，而GFAP表达增加。这些结果表明，AKT信号通路可能在胶质瘤的发生和发展中起重要作用。抗AKT方法将为恶性胶质瘤的靶向分子治疗开辟新的前景。
