Title:Diabetes-specific Modulation of Peripheral Blood Gene Expression Signatures in Colorectal Cancer
VOLUME: 20 ISSUE: 10
Author(s):Zsuzsanna Molnár, Zsófia Bánlaki, Anikó Somogyi, Zoltán Herold, Magdolna Herold, András Guttman, Zsolt Rónai and Gergely Keszler*
Affiliation:Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of Medicine, Semmelweis University, Budapest, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of Medicine, Semmelweis University, Budapest, Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Budapest, 2nd Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Budapest, Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Budapest, Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Doctoral School of Molecular Medicine, Faculty of Medicine, University of Debrecen, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of Medicine, Semmelweis University, Budapest, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of Medicine, Semmelweis University, Budapest
Keywords:Colorectal carcinoma, Type 2 diabetes, Gene expression, RNA, Blood, Biomarker.
Abstract: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.
