Tu1916 SIRT6 As a Regulator for the Metabolic Alterations in Early Colon Carcinogenesis: Further Support for an Early “Warburg-Like” Effect

Background:Generation of genotoxic reactive oxygen species (ROS) in the colon are believed to important in the pathogenesis of colorectal cancer (CRC).There are a number of oxygen scavenging enzymes that are upregulated in response to ROS including Superoxide dismutases (SODs), catalase (CAT) and glutathione peroxidase (GPX).Thus, expression may be a surrogate for the cellular ROS stress.In CRC, mitochondrial Mn-SOD (SOD2) has been overexpressed and shown to encode prognostic information.Our group has focused on evaluating field carcinogenesis as a modality for risk stratification and hence personalization of screening (reviewed in Gastro 2011, Clin Gastro Hep 2012).In the present study, we assayed the mRNA expression of oxygen scavenging enzymes, namely, superoxide dismutases (SOD1, SOD2 and SOD3), catalase (CAT) and glutathione peroxidase (GPX) in the rectal mucosa in patients with and without concomitant colonic neoplasia.Methods:Clinical: Following informed consent, patients (n=64) undergoing screening/surveillance colonoscopy had two biopsies taken from endoscopically normal rectal mucosa.Biomarker: We utilized custom-designed Taqman Low Density Array (TLDA) card and run on ABI Prism 7900HT PCR machine.The predictive ability of the biomarkers was determined through area under the receiver operator characteristic curve (AUROC) of the normalized cycle threshold (Ct) values using Stata 8.0 software.Results:Colonoscopy indicated that 40 patients were neoplasia free whereas 24 harbored adenomas.We noted that in the uninvolved rectal mucosa of the patients with adenomas, there was a dramatic induction of SOD2 (3.9 fold induction, p=0.00366).SOD1, SOD3 and CAT were also induced 2.17, 2.27 and 2.1 fold respectively but with p values of 0.08, 0.053 and 0.076 respectively.There was no change in the GPX expression between adenomas and control patients.Thus, out of the oxygen scavenging enzymes, only Mn-SOD (SOD2) was significantly induced in rectal mucosa of adenoma patients.The diagnostic performance of Mn-SOD was modest with an AUROC of 0.7 although it needs to be emphasized that the majority of adenomas were small which is more challenging from a diagnostic perspective.Conclusion: We demonstrate, for the first time, that SOD 2 was elevated in the pre-dysplastic mucosa and other oxygen scavengers to a lesser extent.This data provides fundamental insights into early events in colon carcinogenesis.Specifically, since expression of these enzymes is "sensor" for ROS, this suggests that ROS may be one of the initiators of colonic neoplasia.From a clinical perspective, these biomarkers had reasonable performance that may be improved with a panel of enzymes or with more significant neoplasia (frank CRCs rather than adenomas).