Landscape of transcriptional deregulation in lung cancer.
Landscape of transcriptional deregulation in lung cancer.
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肺癌转录失调的情况
DOI：
10.1186/s12864-018-4828-1
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发表时间：
2018-06-05
期刊：
影响因子：
4.4
通讯作者：
Fang Z
中科院分区：
文献类型：
--
作者：
Zhang S;Li M;Ji H;Fang Z
肺癌是一种非常异质性的疾病，其可以在病理上分为不同的亚型，包括小细胞肺癌（SCLC）、肺腺癌（LUAD）、肺鳞状细胞癌（LUSC）和大细胞癌（LCC）。虽然已经取得了很大的进展，对每个亚型的致癌机制，转录电路介导的上游信号通路和下游功能的后果仍有待系统研究。本文利用一类支持向量机（OC-SVM）模型建立了一个包含325个转录因子和18724个靶基因的通用转录因子调控网络。然后，我们将该网络应用于肺癌亚型，并确定了那些失调的TF和下游靶点。我们发现TP 63/SOX 2/DMRT 3模块对LUSC是特异性的，对应于鳞状上皮分化和/或存活。此外，LEF 1/MSC模块在LUAD中被特异性激活，并且可能赋予上皮向间充质的转化，这对于癌症恶性进展和转移是重要的。前神经因子ASCL 1在已知具有神经内分泌表型的小细胞肺癌中特异性上调。此外，ID 2在SCLC和LUSC之间差异调节，其在SCLC中的上调与快速有丝分裂的能量供应有关，而其在LUSC中的下调与免疫应答的减弱有关。我们进一步描述了三种主要肺癌亚型中TF调节的情况，突出了它们的功能共性和特异性。我们的方法揭示了肺癌转录失调的景观，并为未来的研究提供了有用的TF调控网络资源。本文的在线版本（10.1186/s12864-018-4828-1）包含补充材料，可供授权用户使用。
Lung cancer is a very heterogeneous disease that can be pathologically classified into different subtypes including small-cell lung carcinoma (SCLC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and large-cell carcinoma (LCC). Although much progress has been made towards the oncogenic mechanism of each subtype, transcriptional circuits mediating the upstream signaling pathways and downstream functional consequences remain to be systematically studied. Here we trained a one-class support vector machine (OC-SVM) model to establish a general transcription factor (TF) regulatory network containing 325 TFs and 18724 target genes. We then applied this network to lung cancer subtypes and identified those deregulated TFs and downstream targets. We found that the TP63/SOX2/DMRT3 module was specific to LUSC, corresponding to squamous epithelial differentiation and/or survival. Moreover, the LEF1/MSC module was specifically activated in LUAD and likely to confer epithelial-to-mesenchymal transition, known important for cancer malignant progression and metastasis. The proneural factor, ASCL1, was specifically up-regulated in SCLC which is known to have a neuroendocrine phenotype. Also, ID2 was differentially regulated between SCLC and LUSC, with its up-regulation in SCLC linking to energy supply for fast mitosis and its down-regulation in LUSC linking to the attenuation of immune response. We further described the landscape of TF regulation among the three major subtypes of lung cancer, highlighting their functional commonalities and specificities. Our approach uncovered the landscape of transcriptional deregulation in lung cancer, and provided a useful resource of TF regulatory network for future studies. The online version of this article (10.1186/s12864-018-4828-1) contains supplementary material, which is available to authorized users.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
4.6
作者：
Han H;Shim H;Shin D;Shim JE;Ko Y;Shin J;Kim H;Cho A;Kim E;Lee T;Kim H;Kim K;Yang S;Bae D;Yun A;Kim S;Kim CY;Cho HJ;Kang B;Shin S;Lee I
通讯作者：
Lee I
影响因子：
5.3
作者：
Lo, Ken C.;Stein, Leighton C.;Hawthorn, Lesleyann
通讯作者：
Hawthorn, Lesleyann
影响因子：
64.8
作者：
Andersson, Lisa S.;Larhammar, Martin;Memic, Fatima;Wootz, Hanna;Schwochow, Doreen;Rubin, Carl-Johan;Patra, Kalicharan;Arnason, Thorvaldur;Wellbring, Lisbeth;Hjalm, Goran;Imsland, Freyja;Petersen, Jessica L.;McCue, Molly E.;Mickelson, James R.;Cothran, Gus;Ahituv, Nadav;Roepstorff, Lars;Mikko, Sofia;Vallstedt, Anna;Lindgren, Gabriella;Andersson, Leif;Kullander, Klas
通讯作者：
Kullander, Klas