Abstract
The deregulated genes in colorectal cancer (CRC) vary significantly across different studies. Thus, a systems biology approach is needed to identify the co-deregulated genes (co-DEGs), explore their molecular networks, and spot the major hub proteins within these networks. We reanalyzed 19 GEO gene expression profiles to identify and annotate CRC versus normal signatures, single-gene perturbation, and single-drug perturbation signatures. We identified the co-DEGs across different studies, their upstream regulating kinases and transcription factors (TFs). Connectivity Map was used to identify likely repurposing drugs against CRC within each group. The functional changes of the co-upregulated genes in the first category were mainly associated with negative regulation of transforming growth factor β production and glomerular epithelial cell differentiation; whereas the co-downregulated genes were enriched in cotranslational protein targeting to the membrane. We identified 17 hub proteins across the co-upregulated genes and 18 hub proteins across the co-downregulated genes, composed of well-known TFs (MYC, TCF3, PML) and kinases (CSNK2A1, CDK1/4, MAPK14), and validated most of them using GEPIA2 and HPA, but also through two signature gene lists composed of the co-up and co-downregulated genes. We further identified a list of repurposing drugs that can potentially target the co-DEGs in CRC, including camptothecin, neostigmine bromide, emetine, remoxipride, cephaeline, thioridazine, and omeprazole. Similar analyses were performed in the co-DEG signatures in single-gene or drug perturbation experiments in CRC. MYC, PML, CDKs, CSNK2A1, and MAPKs were common hub proteins among all studies. Overall, we identified the critical genes in CRC and we propose repurposing drugs that could be used against them.
Highlights
Colorectal cancer (CRC) is the third most common cancer globally and among the most common causes of cancer-related deaths[1]
Using a systems biology approach, we investigated the co-deregulated genes (co-differentially expressed genes (DEGs)) among several independent studies, and categorized them in three groups: (1) in CRC against the adjacent normal mucosa; (2) in CRC tissue or cell lines with a single-gene perturbation against the wild-type tissue or cells; and, (3) in CRC tissue or cell lines with a single-drug perturbation against non-treated tissue or cells
We concluded to such lists of co-DEGs within each of these categories, after stringent filtering and excluding the genes that were deregulated in a single study
Summary
Colorectal cancer (CRC) is the third most common cancer globally and among the most common causes of cancer-related deaths[1]. It is an extremely heterogeneous disease developing through multiple stages and genetic pathways, and consisting of several genetic and epigenetic modifications that lead to malignant transformation of the cells[2]. This heterogeneity is owing to clonal and subclonal mutations randomly dispersed throughout the genome, observed between patients, and among cells within a single tumor mass[3,4].
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