Correlation between Expression Profiles of Key Signaling Genes in Colorectal Cancer Samples from Type 2 Diabetic and Non-Diabetic Patients

Abstract

Several lines of epidemiological and biochemical evidence support the association of type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC). T2DM has been shown to impinge on the transcriptome of colon tumor cells, promoting their proliferation and invasion. In order to gain insight into diabetes-specific modulation of colon cancer signaling, we analyzed gene expression patterns of more than five hundred genes encoding signaling proteins on TaqMan OpenArray panels from colonoscopic colorectal tumor samples of type 2 diabetic and non-diabetic patients. In total, 48 transcripts were found to be differentially expressed in tumors of T2DM patients as compared to healthy colon samples. Enrichment analysis with the g:GOSt (Gene Ontology Statistics) functional profiling tool revealed that the underlying genes can be classified into five signaling pathways (in decreasing order of significance: Wnt (wingless-type)/β-catenin; Hippo; TNF (tumor necrosis factor); PI3K/Akt (phosphoinositide-3 kinase/protein kinase B), and platelet activation), implying that targeted downregulation of these signaling cascades might help combat CRC in diabetic patients. Transcript levels of some of the differentially expressed genes were also measured from surgically removed diabetic and non-diabetic CRC specimens by individual qPCR (quantitative real-time PCR) assays using the adjacent normal tissue mRNA levels as an internal control. The most significantly altered genes in diabetic tumor samples were largely different from those in non-diabetic ones, implying that T2DM profoundly alters the expression of signaling genes and presumably the biological characteristics of CRC.

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“…In the ND-T2D group, the upregulated expression gene enrichment ( p < 0.05) was found in cytokine-cytokine receptor interaction, MAPK signaling pathway, Hippo signaling pathway, TGF-beta signaling pathway, TNF signaling pathway, diabetes AGE-RAGE signaling pathway, IL-17 signaling pathway, ECM-receptor interaction, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway ( Figure 5(a) ). The Hippo signaling pathway regulates cell proliferation and apoptosis to ensure that organ size is normal [ 32 ]. Studies have shown that the imbalance of this pathway may be one of the reasons why T2D patients are more likely to develop tumors [ 33 ], and the MAPK and TGF-beta signaling pathways have also been shown to be considerably related to cell proliferation.…”