Pu P, Zhang Z, Kang C, Jiang R, Jia Z, Wang G, Jiang H
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
Cancer Gene Ther. 2009 Apr;16(4):351-61. doi: 10.1038/cgt.2008.78. Epub 2008 Oct 24.
Increasing evidence suggests that aberrant activation of Wnt signaling is involved in tumor development and progression. Our earlier study on gene expression profile in human gliomas by microarray found that some members of Wnt family were overexpressed. To further investigate the involvement of Wnt signaling in gliomas, the expression of core components of Wnt signaling cascade in 45 astrocytic glioma specimens with different tumor grades was examined by reverse transcription-PCR and immunohistochemistry. Wnt2, Wnt5a, frizzled2 and beta-catenin were overexpressed in gliomas. Knockdown of Wnt2 and its key mediator beta-catenin in the canonical Wnt pathway by siRNA in human U251 glioma cells inhibited cell proliferation and invasive ability, and induced apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous U251 gliomas with siRNA targeting Wnt2 and beta-catenin intratumorally also delayed the tumor growth. In both in vitro and in vivo studies, downregulation of Wnt2 and beta-catenin was associated with the decrease of PI3K/p-AKT expression, indicating the interplay between Wnt/beta-catenin and PI3K/AKT signaling cascades. In conclusion, the canonical Wnt pathway is of critical importance in the gliomagenesis and intervention of this pathway may provide a new therapeutic approach for malignant gliomas.
越来越多的证据表明，Wnt信号通路的异常激活与肿瘤的发生和发展有关。我们早期通过微阵列对人类胶质瘤基因表达谱的研究发现，Wnt家族的一些成员过度表达。为了进一步研究Wnt信号通路在胶质瘤中的作用，我们通过逆转录聚合酶链反应和免疫组织化学检测了45例不同肿瘤分级的星形胶质细胞瘤标本中Wnt信号级联反应核心成分的表达。结果发现，Wnt2、Wnt5a、卷曲蛋白2和β-连环蛋白在胶质瘤中均过度表达。在人U251胶质瘤细胞中，通过小干扰RNA敲低经典Wnt通路中的Wnt2及其关键介质β-连环蛋白，可抑制细胞增殖和侵袭能力，并诱导细胞凋亡。此外，用靶向Wnt2和β-连环蛋白的小干扰RNA对携带已建立的皮下U251胶质瘤的裸鼠进行瘤内注射，也可延缓肿瘤生长。在体外和体内研究中，Wnt2和β-连环蛋白的下调均与PI3K/p-AKT表达的降低有关，这表明Wnt/β-连环蛋白与PI3K/AKT信号级联之间存在相互作用。总之，经典Wnt通路在胶质瘤的发生中至关重要，干预该通路可能为恶性胶质瘤提供一种新的治疗方法。
