Verma Udit N, Surabhi Rama M, Schmaltieg Aurelia, Becerra Carlos, Gaynor Richard B
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Clin Cancer Res. 2003 Apr;9(4):1291-300.
The beta-catenin and APC genes are key components of the Wnt signaling pathway. Mutation of these genes results in increased levels of the beta-catenin protein, which is associated with enhanced cellular proliferation and the development of both colon polyps and colon cancer. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells so that it is now possible to specifically decrease the expression of cellular genes after transfection of annealed small interfering 21-mer RNAs. In the current study, we used small interfering RNA (siRNA) directed against beta-catenin to determine the effects of decreasing the high constitutive levels of this protein in colon cancer cell lines with mutations in either beta-catenin or APC. Our studies demonstrate that siRNA directed against beta-catenin markedly decreased beta-catenin-dependent gene expression and inhibited cellular proliferation as reflected in the reduced growth of these colon cancer cells both in soft agar and in nude mice. These results indicate that siRNA can target specific factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human cancer.
β-连环蛋白和腺瘤性息肉病（APC）基因是Wnt信号通路的关键组成部分。这些基因的突变会导致β-连环蛋白水平升高，这与细胞增殖增强以及结肠息肉和结肠癌的发生有关。最近，一种称为RNA干扰的技术已成功应用于哺乳动物细胞，使得在转染退火的21聚体小干扰RNA后，现在有可能特异性降低细胞基因的表达。在本研究中，我们使用针对β-连环蛋白的小干扰RNA（siRNA）来确定降低β-连环蛋白或APC发生突变的结肠癌细胞系中该蛋白的高组成性水平的影响。我们的研究表明，针对β-连环蛋白的siRNA显著降低了β-连环蛋白依赖性基因的表达，并抑制了细胞增殖，这在软琼脂和裸鼠中这些结肠癌细胞的生长减少中得到了体现。这些结果表明，siRNA可以靶向在恶性肿瘤中表达改变的特定因子，并且可能具有作为治疗人类癌症的治疗方式的潜力。
