Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, CA, USA.
Cancer Res. 2010 Apr 1;70(7):2809-18. doi: 10.1158/0008-5472.CAN-09-4176. Epub 2010 Mar 23.
The minichromosome maintenance (MCM) gene family is essential for DNA replication and is frequently upregulated in various cancers. Here, we examined the role of MCM2 in prostate cancer and the effect of microRNA-1296 (miR-1296), genistein, and trichostatin A (TSA) on the MCM complex. Profiling results showed that expression of MCM genes was higher in tumor samples. Genistein and TSA significantly downregulated the expression of all MCM genes. Genistein, TSA, and small interfering RNA duplexes caused a significant decrease in the S phase of the cell cycle. There was also downregulation of CDT1, CDC7, and CDK2 genes, which govern loading of the MCM complex on chromatin. We also found that miR-1296 was significantly downregulated in prostate cancer samples. In PC3 cells, inhibition of miR-1296 upregulated both MCM2 mRNA and protein, whereas overexpression caused a significant decrease in MCM2 mRNA, protein, and the S phase of the cell cycle. MCM genes are excellent anticancer drug targets because they are essential DNA replication factors that are highly expressed in cancer cells. This is the first report showing anti-MCM effect by miR-1296, genistein, and TSA. TSA is undergoing clinical trials as a prostate cancer treatment but has high toxicity. Genistein, a natural, nontoxic dietary isoflavone, may be an advantageous therapeutic agent for treating prostate cancer. The use of RNA interference is currently being implemented as a gene-specific approach for molecular medicine. The specific downregulation of oncogenes by miR may contribute to novel therapeutic approaches in the treatment of prostate cancer.
微小染色体维持 (MCM) 基因家族对 DNA 复制至关重要，在各种癌症中经常上调。在这里，我们研究了 MCM2 在前列腺癌中的作用，以及 microRNA-1296 (miR-1296)、染料木黄酮和曲古抑菌素 A (TSA) 对 MCM 复合物的影响。分析结果表明，肿瘤样本中 MCM 基因的表达更高。染料木黄酮和 TSA 显著下调所有 MCM 基因的表达。染料木黄酮、 TSA 和小干扰 RNA 双链体导致细胞周期 S 期显著减少。CDT1、CDC7 和 CDK2 基因的下调也会影响 MCM 复合物在染色质上的加载。我们还发现 miR-1296 在前列腺癌样本中显著下调。在 PC3 细胞中，miR-1296 的抑制上调了 MCM2 mRNA 和蛋白，而过表达则导致 MCM2 mRNA、蛋白和细胞周期 S 期显著减少。MCM 基因是极好的抗癌药物靶点，因为它们是高度表达于癌细胞中的必需 DNA 复制因子。这是首次报道 miR-1296、染料木黄酮和 TSA 具有抗 MCM 作用。TSA 正在作为前列腺癌治疗方法进行临床试验，但毒性很高。染料木黄酮是一种天然的、无毒的膳食异黄酮，可能是治疗前列腺癌的有利治疗剂。RNA 干扰的使用目前正在作为一种针对特定基因的方法应用于分子医学。miR 对癌基因的特异性下调可能有助于治疗前列腺癌的新治疗方法。
