Jones Matthew F, Hara Toshifumi, Lal Ashish
Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Division of Virology, Niigata University School of Medicine, Niigata, Japan.
RNA Dis. 2015;2(1). doi: 10.14800/rd.539. Epub 2015 Feb 11.
Human cancers are driven by genetic mutations which cause aberrant activation of pro-growth pathways. Although cancers are uniquely dependent on the pro-growth signaling from oncogenic pathways, efforts to directly target these have been largely unsuccessful. One of the most common and drug resistant oncogenic drivers in colon cancer is the GTPase KRAS. It has been shown that colon cancers with KRAS driver mutations are also 'addicted' to proteins outside of the KRAS pathway due to aberrant re-wiring of cell signaling. A number of genes with a synthetic lethal relationship to mutant KRAS have been previously identified by RNAi screens. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and their expression is frequently dysregulated in cancers. Recently, we have used an innovative functional miRNA screening approach to identify miRNAs that inhibit the survival of KRAS-mutant cells but not KRAS-wild-type cells. MiR-126 was one of the miRNAs that displayed this selective effect. We found that miR-126 induced synthetic lethality in KRAS-Mutant cells via the down-regulation of the polo-like kinase signaling network and a number of genes specifically necessary for the growth of KRAS-Mutant tumors. This study offers a new way forward for exploiting the regulatory power of miRNAs to specifically target aberrant cell signaling in cancer.
人类癌症由基因突变驱动，这些突变会导致促生长途径的异常激活。尽管癌症独特地依赖致癌途径的促生长信号，但直接靶向这些信号的努力大多未成功。结肠癌中最常见且具有耐药性的致癌驱动因子之一是GTP酶KRAS。研究表明，具有KRAS驱动突变的结肠癌由于细胞信号的异常重新布线，也“依赖”于KRAS途径之外的蛋白质。此前通过RNA干扰筛选已鉴定出一些与突变型KRAS具有合成致死关系的基因。微小RNA（miRNA）是基因表达重要的转录后调节因子，其表达在癌症中经常失调。最近，我们使用了一种创新的功能性miRNA筛选方法来鉴定抑制KRAS突变细胞而非KRAS野生型细胞存活的miRNA。MiR-126是表现出这种选择性作用的miRNA之一。我们发现，MiR-126通过下调polo样激酶信号网络以及一些KRAS突变肿瘤生长所必需的特定基因，在KRAS突变细胞中诱导合成致死。这项研究为利用miRNA的调节能力特异性靶向癌症中的异常细胞信号提供了一条新途径。
