School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
State Key Laboratory of Cell Biology, Shanghai, China.
BMC Genomics. 2018 Jun 5;19(1):435. doi: 10.1186/s12864-018-4828-1.
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.
肺癌是一种非常异质性的疾病，可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）。尽管在每个亚型的致癌机制方面已经取得了很大进展，但介导上游信号通路和下游功能后果的转录调控回路仍有待系统研究。
我们使用一类支持向量机（OC-SVM）模型训练了一个通用转录因子（TF）调控网络，该网络包含 325 个 TF 和 18724 个靶基因。然后，我们将该网络应用于肺癌亚型，鉴定出那些失调的 TF 和下游靶基因。我们发现，TP63/SOX2/DMRT3 模块特异性地存在于 LUSC 中，对应于鳞状上皮分化和/或存活。此外，LEF1/MSC 模块特异性地在 LUAD 中激活，可能赋予上皮间质转化，已知这对于癌症恶性进展和转移很重要。神经内分泌表型的 SCLC 中特异性地上调了原神经因子 ASCL1。此外，SCLC 和 LUSC 之间 ID2 的表达存在差异调节，其在 SCLC 中的上调与快速有丝分裂所需的能量供应有关，而在 LUSC 中的下调与免疫反应的减弱有关。我们进一步描述了三种主要肺癌亚型中 TF 调控的全景，突出了它们的功能共性和特异性。
我们的方法揭示了肺癌中转录失调的全景，并为未来的研究提供了一个有用的 TF 调控网络资源。
