Cancer Research, 2010, 70(7):2809-18.

Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer

Shahana Majid, Rajvir Dahiya, et al

Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco; California Pacific Medical Center Research Institute, San Francisco, California

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.

美国《肿瘤研究》，2010年3月

microRNA-1296 和染料木黄酮在前列腺癌中调控微小染色体维持基因

沙哈纳  马吉德，罗杰威 戴海亚等

加利福尼亚大学旧金山退伍军人事务医学中心泌尿外科；加利福尼亚旧金山，加州太平洋医疗中心研究所

微小染色体维持 (MCM) 基因对于 DNA 复制是必需的，在多种癌症中经常表现为表达上调。在这里，我们审查了 MCM2 在前列腺癌中的作用以及微 RNA-1296 (miR-1296)，金雀异黄素和曲古霉素 (TSA) 对 MCM 族群的影响。性能分析结果表明，MCM 基因的表达在肿瘤样本中较高。染料木素和TSA明显下调了所有 MCM 基因的表达。金雀异黄素，TSA，和小干扰 RNA 双链体会造成细胞周期S相的显著减少 。还有 CDT1、 CDC7 和 CDK2 的基因也有所下调，它们控制了染色质上负载的MCM族群。我们还发现，miR-1296年在前列腺癌样品中明显下调。在PC3 细胞中，miR-1296抑制MCM2 mRNA 和蛋白的上调，而过度表达会引起MCM2 mRNA，蛋白质和细胞周期S 相的明显降低。MCM 基因是优良抗癌药物的靶标，因为它们是 DNA 复制的要素，在癌细胞中高度表达。这是第一次展示miR-1296，染料木黄酮和 TSA抗 MCM 效果的报告。TSA 作为一种前列腺癌治疗剂正在进行临床试验，但其具有较高的毒性。染料木黄酮，是一种天然、 无毒的膳食异黄酮，可能有利于前列腺癌的治疗。RNA 干扰目前是分子医学一种特定的基因方法。通过miR使癌基因特定下调可能成为治疗前列腺癌的新治疗方法。