Wlochowitz Darius, Haubrock Martin, Arackal Jetcy, Bleckmann Annalen, Wolff Alexander, Beißbarth Tim, Wingender Edgar, Gültas Mehmet
Institute of Bioinformatics, University Medical Center Göttingen Göttingen, Germany.
Department of Hematology/Medical Oncology, University Medical Center Göttingen Göttingen, Germany.
Front Genet. 2016 Apr 5;7:42. doi: 10.3389/fgene.2016.00042. eCollection 2016.
Transcription factors (TFs) are gene regulatory proteins that are essential for an effective regulation of the transcriptional machinery. Today, it is known that their expression plays an important role in several types of cancer. Computational identification of key players in specific cancer cell lines is still an open challenge in cancer research. In this study, we present a systematic approach which combines colorectal cancer (CRC) cell lines, namely 1638N-T1 and CMT-93, and well-established computational methods in order to compare these cell lines on the level of transcriptional regulation as well as on a pathway level, i.e., the cancer cell-intrinsic pathway repertoire. For this purpose, we firstly applied the Trinity platform to detect signature genes, and then applied analyses of the geneXplain platform to these for detection of upstream transcriptional regulators and their regulatory networks. We created a CRC-specific position weight matrix (PWM) library based on the TRANSFAC database (release 2014.1) to minimize the rate of false predictions in the promoter analyses. Using our proposed workflow, we specifically focused on revealing the similarities and differences in transcriptional regulation between the two CRC cell lines, and report a number of well-known, cancer-associated TFs with significantly enriched binding sites in the promoter regions of the signature genes. We show that, although the signature genes of both cell lines show no overlap, they may still be regulated by common TFs in CRC. Based on our findings, we suggest that canonical Wnt signaling is activated in 1638N-T1, but inhibited in CMT-93 through cross-talks of Wnt signaling with the VDR signaling pathway and/or LXR-related pathways. Furthermore, our findings provide indication of several master regulators being present such as MLK3 and Mapk1 (ERK2) which might be important in cell proliferation, migration, and invasion of 1638N-T1 and CMT-93, respectively. Taken together, we provide new insights into the invasive potential of these cell lines, which can be used for development of effective cancer therapy.
转录因子（TFs）是基因调控蛋白，对于有效调控转录机制至关重要。如今，已知它们的表达在多种癌症类型中发挥重要作用。在癌症研究中，计算识别特定癌细胞系中的关键因子仍是一个悬而未决的挑战。在本研究中，我们提出了一种系统方法，该方法结合了结肠直肠癌（CRC）细胞系，即1638N-T1和CMT-93，以及成熟的计算方法，以便在转录调控水平以及通路水平，即癌细胞内在通路库上比较这些细胞系。为此，我们首先应用Trinity平台检测特征基因，然后将geneXplain平台的分析应用于这些基因，以检测上游转录调节因子及其调控网络。我们基于TRANSFAC数据库（2014.1版）创建了一个CRC特异性位置权重矩阵（PWM）库，以尽量减少启动子分析中的错误预测率。使用我们提出的工作流程，我们特别专注于揭示两种CRC细胞系在转录调控方面的异同，并报告了一些在特征基因启动子区域具有显著富集结合位点的、与癌症相关的知名TFs。我们表明，尽管两种细胞系的特征基因没有重叠，但它们在CRC中仍可能受共同的TFs调控。基于我们的发现，我们认为经典Wnt信号通路在1638N-T1中被激活，但在CMT-93中通过Wnt信号通路与VDR信号通路和/或LXR相关通路的相互作用而被抑制。此外，我们的发现表明存在几种主调控因子，如MLK3和Mapk1（ERK2），它们可能分别在1638N-T1和CMT-93的细胞增殖、迁移和侵袭中起重要作用。综上所述，我们为这些细胞系的侵袭潜力提供了新的见解，可用于开发有效的癌症治疗方法。
