Abstract
BackgroundColon cancer occurrence is increasing worldwide, making it the third most frequent cancer. Although many therapeutic options are available and quite efficient at the early stages, survival is strongly decreased when the disease has spread to other organs. The identification of molecular markers of colon cancer is likely to help understanding its course and, eventually, to uncover novel genes to be targeted by drugs. In this study, we compared gene expression in a set of 95 human colon cancer samples to that in 19 normal colon mucosae, focusing on 401 genes from 5 selected pathways (Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism, Wnt/beta-catenin). Deregulation of mRNA levels largely matched that of proteins, leading us to build in silico protein networks, starting from mRNA levels, to identify key proteins central to network activity.ResultsAmong the analyzed genes, 10.5% (42) had no reported link with colon cancer, including the SFRP1, IGF1 and ADH1B (down), and MYC and IL8 (up), whose encoded proteins were most interacting with other proteins from the same or even distinct networks. Analyzing all pathways globally led us to uncover novel functional links between a priori unrelated or rather remotely connected pathways, such as the Drug metabolism and the Cancer pathways or, even more strikingly, between the Cholesterol metabolism and lipoprotein signaling and the Cancer pathways. In addition, we analyzed the responsiveness of some of the deregulated genes essential to network activities, to chemotherapeutic agents used alone or in presence of Lovastatin, a lipid-lowering drug. Some of these treatments could oppose the deregulations occurring in cancer samples, including those of the CHECK2, CYP51A1, HMGCS1, ITGA2, NME1 or VEGFA genes.ConclusionsOur network-based approach allowed discovering genes not previously known to play regulatory roles in colon cancer. Our results also showed that selected drug treatments might revert the cancer-specific deregulation of genes playing prominent roles within the networks operating to maintain colon homeostasis. Among those genes, some could constitute novel testable targets to eliminate colon cancer cells, either directly or, potentially, through the use of lipid-lowering drugs such as statins, in association with selected anticancer drugs.
Highlights
Colon cancer occurrence is increasing worldwide, making it the third most frequent cancer
We treated human CRC cell lines by anticancer drugs alone or in combination with Lovastatin, a cholesterol-lowering drug that can efficiently trigger apoptosis, and analyzed marker gene expression in response to the drugs. This led us to sort out genes that responded to treatments in a way that would lead to restoring gene expression as it stands in non-cancerous cells
The strongest increase in gene expression in CRC vs. normal tissue (NT) was for the IL8 gene in paired samples (25.8-fold, 16-fold for unpaired), whereas the largest decrease was −10.5-fold for ADH1B in paired samples (−14.7-fold for unpaired)
Summary
Colon cancer occurrence is increasing worldwide, making it the third most frequent cancer. A recent study analyzed a reported data set distinguishing colon cancer from healthy samples with the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and built a protein-protein interaction network using the Cytoscape environment [6] Such a network analysis allowed identifying central proteins, or hubs, belonging to overor under-represented pathways. These assays analyzed the Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism and Wnt/beta-catenin pathways Such a PCR-based approach, of relatively low throughput, has the advantage to allow investigating directly, in a robust and straightforward analysis, the expression of genes involved in a given functional pathway, in this case most linked to cancer. We believe that this work based on an integrative approach, in addition to identifying new deregulated gene expression networks in colon cancer, highlighted some interactions between the protein products of these genes, and identified genes whose cancer-specific expression could be reverted by pharmacological agents already used in the treatment of patients, or that may be so by other drugs like Lovastatin
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