Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data.
Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data.
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DOI：
10.1371/journal.pone.0196351
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Zhang T;Xu J;Deng S;Zhou F;Li J;Zhang L;Li L;Wang QE;Li F
超过70%的卵巢癌患者会发生肿瘤复发，大多数最终变得难以治疗。卵巢癌干细胞（OCSCs）被认为是肿瘤复发和耐药性的原因。因此，清除卵巢CSC对改善卵巢癌患者的预后至关重要。然而，由于调控OCSC的核心信号通路尚不清楚，因此缺乏有效的药物来消除OCSC。此外，生物学家通常很难以无偏的方式从大量差异表达的基因中鉴定一些可测试的靶标并推断调控CSC的驱动信号通路。在这项研究中，我们提出了一个简单的和综合的分析，以确定潜在的核心信号通路的OCSC整合转录组数据分离基于两个独特的标志物，ALDH和侧人口，调控网络（转录因子（TF）和目标相互作用组）和信号通路。我们首先确定了两个OCSC群体中整合基因表达和TF-靶相互作用组的常见活化TF;然后揭示了调节活化TF的上游信号级联。具体而言，鉴定了22个活化的TF。通过文献检索验证，其中15个与癌症干细胞相关。此外，在KEGG信号通路中发现了10个TF，并提取了它们的上游信号级联，这也提供了潜在的治疗靶点。此外，FDA批准的40种药物被鉴定为靶向上游信号级联，其中15种已在癌症干细胞治疗的文献中报道。总之，所提出的方法可以揭示激活的上游信号，激活的TF和上调的靶基因，构成了卵巢CSC的潜在核心信号通路。靶向核心信号通路的药物和药物组合也可能能够消除OCSC。所提出的方法也可以应用于识别其他类型癌症的潜在激活信号通路。
Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers.
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DOI：
10.1093/bioinformatics/btu278
发表时间：
2014-06-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Huang L;Li F;Sheng J;Xia X;Ma J;Zhan M;Wong ST
通讯作者：
Wong ST
影响因子：
4.3
作者：
Della Corte CM;Viscardi G;Papaccio F;Esposito G;Martini G;Ciardiello D;Martinelli E;Ciardiello F;Morgillo F
通讯作者：
Morgillo F
影响因子：
--
作者：
Fisher, RA
通讯作者：
Fisher, RA
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
14.9
作者：
Han H;Cho JW;Lee S;Yun A;Kim H;Bae D;Yang S;Kim CY;Lee M;Kim E;Lee S;Kang B;Jeong D;Kim Y;Jeon HN;Jung H;Nam S;Chung M;Kim JH;Lee I
通讯作者：
Lee I