MicroRNAs in cancer pharmacology and therapeutics: exploiting a natural synergy between '-omic' and hypothesis-driven research.
MicroRNAs in cancer pharmacology and therapeutics: exploiting a natural synergy between '-omic' and hypothesis-driven research.
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癌症药理学和治疗学中的 MicroRNA：利用“组学”和假设驱动研究之间的自然协同作用。
DOI：
10.1158/1535-7163.mct-11-0766
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发表时间：
2011
影响因子：
5.7
通讯作者：
Weinstein,JohnN
中科院分区：
文献类型：
--
作者：
Weinstein,JohnN
2008年，我们在这本杂志上报道了第一个关于microRNA对癌细胞药物活性影响的广泛研究。由于microRNA先前已被证明会影响发育、致癌、细胞存活和凋亡等过程，因此它们似乎也会调节抗癌药物的敏感性和耐药性。为了验证这一假设，我们首先分析了我们之前通过NCI-60分子谱获得的数据集中的药物-microRNA相关性，NCI-60是美国国家癌症研究所用于筛选抗癌活性化合物的癌细胞系组（1）。由于NCI-60已经在DNA，mRNA和蛋白质水平上进行了比任何其他细胞更广泛的分析（2），我们的优势是将我们对microRNA的发现置于这些多个额外表征的背景下。通过相当严格的统计学标准，大约30种microRNA与各种抗癌药物显示出高度显著的相关性。如MCT文章中所报道的，我们随后在来自NCI-60组的3种不同细胞系中对先前与癌症生物学有关的3种microRNA（let-7i、mir-16和mir-21）进行了集中的药理学研究。在我们的实验系统中，单个microRNA的表达通过用它们的前体（其是活性的）阻断细胞而增加，或者通过用反义寡聚体阻断细胞而抑制。总体而言，我们评估了14个化合物的结构和功能多样性的生长抑制效力。改变let-7i、mir-16和mir-21的水平会影响许多抗癌药物的效力，影响程度高达4倍。这种作用在mir-21中最为突出; 28个细胞-化合物对中有10个显示出生长抑制活性的显著变化。不同的mir-21水平会根据药剂的类别以相反的方向改变效力，表明毒性和保护作用机制的差异。总的来说，这些结果支持microRNA在抗癌药物反应中的重要作用，并提出了改善化疗结果的新的潜在方法。研究中的概念和发现已经被许多研究人员跟进。近100篇引用它的论文包括MCT（3）和其他AACR期刊（4）的重要出版物。该研究发表在MCT的“聚焦分子特征分析”系列（5）中，该系列由编辑于2005年建立，以突出具有癌细胞及其药理学的全面分子特征的出版物。这一系列预示着目前的项目，如癌症基因组图谱企业，正在做同样的临床癌症。在这样做的过程中，该系列强调了组学和假设驱动的研究之间的自然协同作用。衷心祝贺MCT成立十周年，它对癌症药理学和治疗学的洞察力，远见和开创性贡献。
In 2008 in this journal, we reported the first broad-based study of the impact of microRNAs on drug activity in cancer cells. Because microRNAs had previously been shown to influence such processes as development, carcinogenesis, cell survival, and apoptosis, it seemed likely that they would also modulate sensitivity and resistance to anticancer drugs. To test that hypothesis, we first analyzed drug–microRNA correlations in data sets we had previously obtained by molecular profiling of the NCI-60, a cancer cell line panel used by the National Cancer Institute to screen compounds for anticancer activity (1). Because the NCI-60 had already been profiled at the DNA, mRNA, and protein levels more extensively than had any other set of cells (2), we had the advantage of placing our findings for microRNAs in the context of those multiple additional characterizations. Approximately 30 microRNAs showed highly significant correlations with various anticancer agents by quite stringent statistical criteria. As reported in the MCT article, we then followed up with focused pharmacologic studies of 3 microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) in 3 diverse cell lines from the NCI-60 set. In our experimental system, the expression of individual microRNAs was increased by transfecting the cells with their precursors (which are active) or suppressed by transfecting the cells with antisense oligomers. Overall, we assessed the growth-inhibitory potencies of 14 compounds selected for structural and functional diversity. Altering the levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to fourfold. The effect was most prominent with mir-21; 10 of 28 cell-compound pairs showed significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on the class of the agent, indicating differences in mechanism of toxic and protective effects. Overall, the results supported a substantial role for microRNAs in anticancer drug response and suggested novel potential approaches for improving the results of chemotherapy. Conceptsandfindingsinthestudyhavebeenfollowedup by numerous investigators. The almost 100 papers citing it have included prominent publications inMCT (3) and other AACR journals (4). The study was published in MCT’s" Spotlight on Molecular Profiling" series (5), which was established by the Editors in 2005 to highlight publications that feature comprehensive molecular characterization of cancer cells and their pharmacology. The series presaged current projects like The Cancer Genome Atlas enterprise that are doing the same for clinical cancers. In doing so, the series highlighted a natural synergy between-omic and hypothesis-drivenresearch. HeartycongratulationstoMCT on its tenth anniversary of insight, foresight, and seminal contributions to cancer pharmacology and therapeutics.