Diabetes-mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction

Type 2 diabetes mellitus (T2DM) has been associated with an increased riskof cancer, including colon cancer (CC). However, we recently reported noinfluence of T2DM on CC prognosis, suggesting that any effect might be atthe early stages of tumor development. We hypothesized that T2DM maycreate an environment in the healthy tissue, which acts as a carcinogenesisdriver in agreement with the field of cancerization concept. Here, we focusedon early carcinogenesis by analyzing paired tumor and normal colonicmucosa samples from the same patients. The proteome of CC and pairedmucosa was quantitatively analyzed in 28 individuals (12 diabetics and 16nondiabetics) by mass spectrometry with isobaric labeling. Out of 3076 identifiedproteins, 425 were differentially expressed at the tumor in diabeticscompared with nondiabetics. In the adjacent mucosa, 143 proteins were differentiallyexpressed in diabetics and nondiabetics. An enrichment analysisof this signature pointed to mitochondria, ribosome, and translation. Onlysix proteins were upregulated by diabetes both in tumor and mucosa, ofwhich five were mitochondrial proteins. Differential expression in diabeticversus nondiabetic mucosa was confirmed for MRPL53, MRPL18, andTIMM8B. Higher levels of MRPL18, TIMM8B, and EIF1A were also foundin normal colon epithelial cells exposed to high-glucose conditions. We concludethat T2DM is associated with specific molecular changes in the normalmucosa of CC patients, consistent with field of cancerization in a diabeticenvironment. The mitochondrial protein signature identifies a potential therapeutictarget that could underlie the higher risk of CC in diabetics.