Diabetes-specific Modulation of Peripheral Blood Gene Expression Signatures in Colorectal Cancer

Background: Type 2 diabetes (T2DM) and colorectal cancer (CRC) are both known to modulate gene expression patterns in peripheral blood leukocytes (PBLs). Objective: As T2DM has been shown to increase the incidence of CRC, we were prompted to check whether diabetes affects mRNA signatures in PBLs isolated from CRC patients. Methods: Twenty-two patients were recruited to the study and classified into four cohorts (healthy controls; T2DM; CRC; CRC and T2DM). Relative expression levels of 573 cell signaling gene transcripts were determined by reverse transcription real-time PCR assays run on low-density OpenArray platforms. Enrichment analysis was performed with the g:GOSt profiling tool to order differentially expressed genes into functional pathways. Results: 49 genes were found to be significantly up- or downregulated in tumorous diabetic individuals as compared to tumor-free diabetic controls, while 11 transcripts were differentially regulated in patients with CRC versus healthy, tumor-free and nondiabetic controls. Importantly, these gene sets were completely distinct, implying that diabetes exerts a profound influence on the transcription of signaling genes in CRC. The top 5 genes showing the most significant expression differences in both contexts were PCK2, MAPK9, CCND1, HMBS, TLR3 (p≤0.0040) and CREBBP, PPIA, NFKBIL1, MDM2 and SELPLG (p≤0.0121), respectively. Functional analysis revealed that most significantly affected pathways were cytokine, interleukin and PI3K/Akt/mTOR signaling cascades as well as mitotic regulation. Conclusion: We propose that differentially expressed genes listed above might be potential biomarkers of CRC and should be studied further on larger patient groups. Diabetes might promote colorectal carcinogenesis by impairing signaling pathways in PBLs.