From NPC Therapeutic Target Identification to Potential Treatment Strategy
From NPC Therapeutic Target Identification to Potential Treatment Strategy
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DOI：
10.1158/1535-7163.mct-09-0966
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发表时间：
2010-09-01
影响因子：
5.7
通讯作者：
Huang, Chi-Ying F.
中科院分区：
文献类型：
--
作者：
Lan, Ming-Ying;Chen, Chi-Long;Huang, Chi-Ying F.
鼻咽癌（NPC）在西方国家相对罕见，但在南亚是一种常见的癌症。许多差异表达的基因与NPC有关;然而，如何从未分类的基因列表中优先考虑治疗靶点和潜在药物仍然是未知的。我们首先从已发表的基因芯片数据和原始文献中收集了558个上调和993个下调的NPC基因。然后，我们假设，将基因签名转换为蛋白质-蛋白质相互作用网络，并对网络进行拓扑分析，可以深入了解参与NPC肿瘤发生的关键调控因子。特别感兴趣的是在推断的NPC网络中存在被称为全连通子图的集团。这些基于cnc的枢纽，与三个以上的查询连接，并且在NPC蛋白质-蛋白质相互作用网络中排名高于其他节点，通过通路分析进一步缩小范围，以检索24个上调和6个下调的瓶颈基因用于预测NPC致癌。此外，额外的癌基因，肿瘤抑制基因，蛋白质复合物中涉及的基因，和功能分析后获得的基因与瓶颈基因合并，形成38个上调和10个下调基因的最终基因签名。我们使用初始和最终NPC基因签名分别查询连接图，发现通过我们的管道进行靶点减少可以有效地发现对NPC癌细胞具有细胞毒性的潜在药物。建立了一个综合性的网站（http：//140.109.23.188：8080/NPC），以促进未来NPC的研究。这种从靶点优先到潜在药物鉴定的计算机方法可能是各种癌症研究的有效方法。Mol Cancer Ther; 9（9）; 2511-23. (C)2010年AACR。
Nasopharyngeal carcinoma (NPC) is relatively rare in Western countries but is a common cancer in southern Asia. Many differentially expressed genes have been linked to NPC; however, how to prioritize therapeutic targets and potential drugs from unsorted gene lists remains largely unknown. We first collected 558 upregulated and 993 downregulated NPC genes from published microarray data and the primary literatures. We then postulated that conversion of gene signatures into the protein-protein interaction network and analyzing the network topologically could provide insight into key regulators involved in tumorigenesis of NPC. Of particular interest was the presence of cliques, called fully connected subgraphs, in the inferred NPC networks. These clique-based hubs, connecting with more than three queries and ranked higher than other nodes in the NPC protein-protein interaction network, were further narrowed down by pathway analysis to retrieve 24 upregulated and 6 downregulated bottleneck genes for predicting NPC carcinogenesis. Moreover, additional oncogenes, tumor suppressor genes, genes involved in protein complexes, and genes obtained after functional profiling were merged with the bottleneck genes to form the final gene signature of 38 upregulated and 10 downregulated genes. We used the initial and final NPC gene signatures to query the Connectivity Map, respectively, and found that target reduction through our pipeline could efficiently uncover potential drugs with cytotoxicity to NPC cancer cells. An integrative Web site (http://140.109.23.188:8080/NPC) was established to facilitate future NPC research. This in silico approach, from target prioritization to potential drugs identification, might be an effective method for various cancer researches. Mol Cancer Ther; 9(9); 2511-23. (C) 2010 AACR.