Computational Identification of Key Regulators in Two Different Colorectal Cancer Cell Lines

Abstract

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.

Identification of Age-Specific and Common Key Regulatory Mechanisms Governing Eggshell Strength in Chicken Using Random Forests

“…Following our previous studies [39,40], we performed the "upstream analysis" and pathway analysis using the geneXplain platform [41] to gain more insight into the functional relationships of genes. The algorithm of "upstream analysis" workflow was introduced by Koschmann et al [42] and its main goal is to reveal the underlying key regulators that control the activity of target genes.…”

PI3K: A master regulator of brain metastasis‐promoting macrophages/microglia

“…Master regulator analysis based on CTL-and BKM-DEG sets was performed as previously described (Wlochowitz et al, 2016) using standard workflows of the geneXplain platform (http://genexplain.com/). Master regulatory networks were generated based on the TRANS-PATH 2017.1 pathway knowledge (Choi et al, 2004).…”

Molecular Cytogenetic Characterization of Two Murine Colorectal Cancer Cell Lines

“…Colorectal cancer (CRC) is the third most common human cancer worldwide and the fourth most common cause of cancer-related deaths in adults [1]. Mutations in specific genes, like oncogenes, tumor suppressor genes, and genes related to DNA-repair mechanisms, can lead to the onset of CRC [2].…”

“…According to the classification of the Union International Contre Le Cancer (UICC), the four stages of CRC are distinguished as follows: (I) limitation on the intestinal wall; (II) growth beyond the intestinal wall; (III) lymphatic metastasis; and (IV) distant metastases, mainly in liver or lung [5]. With the elucidation of the molecular pathways involved in tumorigenesis, novel models of human-cancer development have been created to further advance our understanding of CRC, increase our ability to evaluate potential therapies, and positively affect patients' outcomes [1,6].…”

“…Thus, murine models have been extensively used in cancer studies (e.g. to directly monitor the metastatic progression in CRCs) [1]. In addition to the mouse as a whole organism and the development of embryonic stem cell lines, murine tumor cell lines were introduced into research in the 1970s [7,8].…”