Pulukuri Sai Murali Krishna, Rao Jasti S
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, USA.
Cancer Res. 2007 Jul 15;67(14):6637-46. doi: 10.1158/0008-5472.CAN-07-0751.
Recent studies have shown that small interfering RNA (siRNA) silences genes at the transcriptional level in human cells. However, the therapeutic potential of siRNA-mediated transcriptional gene silencing remains unclear. Here, we show that siRNA targeted to the urokinase plasminogen activator (uPA) promoter induced epigenetic transcriptional silencing in human prostate cancer cells. This silencing resulted in a dramatic reduction of tumor cell invasion and angiogenesis in vitro. Furthermore, the results from a bioluminescence tumor/metastasis model showed that the silencing of uPA significantly inhibits prostate tumor growth and the incidence of lung metastasis. Our findings represent a potentially powerful new approach to not only epigenetic silencing of metastasis or growth-promoting genes as a cancer therapy, but also as a means to shed light on how aberrant de novo methylation during cancer progression might be targeted to specific sequences.
最近的研究表明，小干扰RNA（siRNA）在人类细胞中可在转录水平使基因沉默。然而，siRNA介导的转录基因沉默的治疗潜力仍不清楚。在此，我们表明靶向尿激酶型纤溶酶原激活剂（uPA）启动子的siRNA可在人前列腺癌细胞中诱导表观遗传转录沉默。这种沉默导致体外肿瘤细胞侵袭和血管生成显著减少。此外，生物发光肿瘤/转移模型的结果表明，uPA的沉默显著抑制前列腺肿瘤生长和肺转移发生率。我们的发现不仅代表了一种潜在的强大新方法，可将转移或生长促进基因的表观遗传沉默作为癌症治疗手段，还代表了一种揭示癌症进展过程中异常从头甲基化如何靶向特定序列的方法。
