Abstract
Precise characterization of biological processes critical to proliferation and metastasis of colorectal cancer should facilitate the development of diagnostic and prognostic biomarkers as well as novel treatments. Using mRNA-Seq, we examined the protein coding messenger RNA (mRNA) expression profiles across different histologically defined stages of primary colon cancers and compared them to their patient matched normal tissue controls. In comparing 79 colorectal cancers to their matched normal mucosa, tumors were distinguished from normal non-malignant tissues not only in the upregulation of biological processes pertaining to cell proliferation, inflammation, and tissue remodeling, but even more strikingly, in downregulated biological processes including fatty acid beta oxidization for ATP production and epithelial cell differentiation and function. A network analysis of deregulated genes revealed newly described cancer networks and putative hub genes.Taken together, our findings suggest that, within an inflammatory microenvironment, invasive, dedifferentiated and rapidly dividing tumor cells divert the oxidation of fatty acids and lipids from energy production into lipid components of cell membranes and organelles to support tumor proliferation. A gene co-expression network analysis provides a clear and broad picture of biological pathways in tumors that may significantly enhance or supplant current histopathologic studies.
Highlights
Colorectal cancer is the third most common cancer and the third most common cause of cancer-related deaths in men and women in the United States [1]
In comparing 79 colorectal cancers to their matched normal mucosa, tumors were distinguished from normal nonmalignant tissues in the upregulation of biological processes pertaining to cell proliferation, inflammation, and tissue remodeling, but even more strikingly, in downregulated biological processes including fatty acid beta oxidization for ATP production and epithelial cell differentiation and function
Unsupervised hierarchical clustering analysis (HCA) of these 2,358 genes showed that normal samples and one low stage tumor sample clustered into a distinct group while tumor samples and 2 normal samples associated with high stage tumors clustered into another group (Figure 1B)
Summary
Colorectal cancer is the third most common cancer and the third most common cause of cancer-related deaths in men and women in the United States [1]. Immunohistochemical staining [3] and microarray analyses [4] have shown that cancer cells, unlike their healthy tissue counterparts, switch from aerobic mitochondrial oxidative phosphorylation to glycolysis (The Warburg Effect) as the www.impactjournals.com/oncotarget primary energy source even in the context of an aerobic microenvironment. Glycolysis provides cancer cells with energy, and with metabolites including ribose sugars, glycerol, citrate, and nonessential amino acids which are essential for cellular proliferation [5,6,7]. We identified cancer specific gene expression patterns and cancer associated signaling and regulatory pathways in colorectal cancer samples as compared to their patient matched healthy colonic tissues using mRNA-Seq. Our study sought to explore expression correlations among dysregulated genes pertaining to biological pathways critical in tumor proliferation and metastasis by identifying and quantifying critical mRNA gene co-expression networks and hub genes
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