Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway

Canli, Secil Demirkol
Seza, Esin Gulce
Sheraj, Ilir
Gomceli, Ismail
Turhan, Nesrin
Carberry, Steven
Prehn, Jochen H. M.
Banerjee, Sreeparna
AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1(HIGH)) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1(HIGH) was associated with worse overall survival (OS) compared with patients with low expression of AKR1B1 (AKR1B1(LOW)) samples. A combined signature of AKR1B1(HIGH) and AKR1B10(LOW) was significantly associated with worse recurrence-free survival (RFS) in microsatellite stable (MSS) patients and in patients with distal colon tumors as well as a higher mesenchymal signature when compared with AKR1B110(LOW)/AKR1B10(HIGH) tumors. When the patients were stratified according to consensus molecular subtypes (CMS), AKR1B1(HIGH)/AKR1B10(LOW) samples were primarily classified as CMS4 with predominantly mesenchymal characteristics while AKR1B1(LOW)/AKR1B10(HIGH) samples were primarily classified as CMS3 which is associated with metabolic deregulation. Reverse Phase Protein Array carried out using protein samples from the Ankara cohort indicated that AKR1B1(HIGH)/AKR1B10(LOW) tumors showed aberrant activation of metabolic pathways. Western blot analysis of AKR1B1(HIGH)/AKR1B10(LOW) colon cancer cell lines also suggested aberrant activation of nutrient-sensing pathways. Collectively, our data suggest that the AKR1B1(HIGH)/AKR1B10(LOW) signature may be predictive of poor prognosis, aberrant activation of metabolic pathways, and can be considered as a novel biomarker for colon cancer prognostication.


Evaluation of functional changes in akr1b1 and akr1b10 overexpressing colorectal cancer cell lines
Güderer, İsmail; Banerjee, Sreeparna; Department of Biology (2021-2-15)
Aldo-keto reductases (AKRs) are nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzymes with diverse cellular metabolism functions. AKR1B1 and AKR1B10 are two of the most studied enzymes in the AKR family. AKR1B1 reduces excess glucose into sorbitol using reducing electrons from NADPH, and the hyperactivation of the AKR1B1 pathways is associated with oxidative stress and cell death. AKR1B10 is a poor reductant of glucose but is a vital enzyme that can metabolize retinol and many other drugs an...
Investigation of the inflammatory pathways in spontaneously differentiating Caco-2 cells
Astarcı, Erhan; Banerjee, Sreeparna; Çoruh, Nursen; Department of Biochemistry (2011)
Intestinal epithelial differentiation entails the formation of highly specialized cells with specific absorptive, secretory, digestive and immune functions. Cell-cell and cell-microenvironment interactions appear to be crucial in determining the outcome of the differentiation process. Using the Caco-2 cell line that can undergo spontaneous differentiation when grown past confluency, we observed a loss of VCAM1 (vascular cell adhesion molecule-1) expression while ICAM1 (intercellular cell adhesion molecule-1...
Significance of genetic Polymorphisms at multiple loci of CYP2E1 in the risk of development of childhood acute lymphoblastic leukemia
Ulusoy, Gulen; Adalı, Orhan; Tumer, Tugba Boyunegmez; Sahin, Gurses; Gozdasoglu, Sevgi; Arinc, Emel (S. Karger AG, 2007-01-01)
Background/Aims: The molecular etiology of childhood acute lymphoblastic leukemia (ALL) is likely to involve interactions between environmental factors and genetic make up. Understanding these interactions between various predisposing genes for the risk of developing childhood leukemia is of considerable importance. CYP2E1 is a susceptible gene in this respect, especially for its capacity to bioactivate many procarcinogens including benzene and N-nitrosodimethylamine. The CYP2E1 gene possesses several polym...
Emerging cellular functions of the lipid metabolizing enzyme 15-Lipoxygenase-1
Colakoglu, Melis; Tuncer, Sinem; Banerjee, Sreeparna (Wiley, 2018-10-01)
The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15-LOX-1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has been shown to...
Investigation of the effect of sodium butyrate on the regulation of cyclooxygenase-2 in colon cancer cell lines Caco-2 and HT-29
Ülgen, Doğukan Hazar; Banerjee, Sreeparna; Department of Biology (2015)
Sodium butyrate (NaBt) is a four-carbon short-chain fatty acid histone deacetylase inhibitor (HDACi) that is available in the colon through the commensal microbiota-mediated fermentation of dietary fibers. It is the main source of energy for colonocytes, and is regarded to have tumor suppressive effects, most prominently in colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is a gene important in the inflammatory response due to its ability to convert arachidonic acid to prostaglandins. Overexpression and ov...
Citation Formats
S. D. Canli et al., “Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway,” CARCINOGENESIS, pp. 1219–1228, 2020, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/69978.