Genome-wide mRNA and microRNA profiling of the NCI 60 cell-line screen and comparison of FdUMP[10] with fluorouracil, floxuridine, and topoisomerase 1 poisons.
Genome-wide mRNA and microRNA profiling of the NCI 60 cell-line screen and comparison of FdUMP[10] with fluorouracil, floxuridine, and topoisomerase 1 poisons.
复制标题
NCI 60细胞系筛选的全基因组mRNA和microRNA分析以及Fdump [10]与氟尿嘧啶，氟乙胺和拓扑异构酶1毒物的比较。
DOI：
10.1158/1535-7163.mct-10-0674
复制
发表时间：
2010-12
影响因子：
5.7
通讯作者：
Pommier Y
中科院分区：
文献类型：
--
作者：
Gmeiner WH;Reinhold WC;Pommier Y
分析了整个NCI-60细胞系筛选中的microRNA和mRNA表达模式谱，以鉴定与对FdUMP[10]、氟尿嘧啶（5 FU）、阿糖胞苷（FdU）、拓扑替康和伊立替康敏感性相关的表达特征。全基因组图谱分析显示FdUMP[10]与FdU最接近，并与5 FU表现出不同之处。FdUMP[10]在NCI-60中具有任何这些药物的最大动态范围，表明癌细胞特异性活性。参与内吞作用的基因，如网格蛋白（CLTC-1）、SNF 8、膜联蛋白A6（ANXA 6）和淀粉样蛋白结合2（APPBP 2），与FdUMP敏感性独特相关[10]，与蛋白介导的FdUMP细胞摄取一致[10]。参与核苷酸代谢的基因富集了三种氟嘧啶药物，5 FU的表达谱与RNA介导的细胞毒性机制相关，而利用UDP-糖作为底物的糖基转移酶（XYLT 2）和核苷二磷酸酶和转移抑制因子NM 23（NME 1）的表达与FdUMP敏感性相关[10]。托泊替康和伊立替康与miR-24（一种具有Top1高聚合PCT评分的microRNA）具有显著负相关性。我们的研究结果揭示了FdUMP[10]和Top1-毒物之间的显著新相关性，以及关于FdUMP[10]的独特细胞毒性机制和基因组特征的新信息。
A profile of microRNA and mRNA expression patterns across the NCI-60 cell line screen was analyzed to identify expression signatures that correlate with sensitivity to FdUMP[10], fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP[10] resembles FdU most closely and shows dissimilarities with 5FU. FdUMP[10] had the largest dynamic range of any of these drugs across the NCI-60 indicative of cancer cell-specific activity. Genes involved in endocytosis, such as clathrin (CLTC-1), SNF8, annexin A6 (ANXA6) and amyloid protein-binding 2 (APPBP2) uniquely correlated with sensitivity to FdUMP[10], consistent with a protein-mediated cellular uptake of FdUMP[10]. Genes involved in nucleotide metabolism were enriched for the three fluoropyrimidine drugs, with the expression profile for 5FU correlated to an RNA-mediated cytotoxic mechanism, while expression of glycosyltransferases (XYLT2) that utilize UDP-sugars as substrates and the nucleoside diphosphatase and metastasis suppressor NM23 (NME1) were associated with FdUMP[10] sensitivity. Topotecan and irinotecan had significant negative correlations with miR-24, a microRNA with a high aggregate PCT score for Top1. Our results reveal significant new correlations between FdUMP[10] and Top1-poisons as well as new information on the unique cytotoxic mechanism and genomic signature of FdUMP[10].