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

ABSTRACT: Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of cancer, including colon cancer (CC). However, we recently reported no influence of T2DM on CC prognosis, suggesting that any effect might be at the early stages of tumor development. We hypothesized that T2DM may create an environment in the healthy tissue, which acts as a carcinogenesis driver in agreement with the field of cancerization concept. Here, we focused on early carcinogenesis by analyzing paired tumor and normal colonic mucosa samples from the same patients. The proteome of CC and paired mucosa was quantitatively analyzed in 28 individuals (12 diabetics and 16 nondiabetics) by mass spectrometry with isobaric labeling. Out of 3076 identified proteins, 425 were differentially expressed at the tumor in diabetics compared with nondiabetics. In the adjacent mucosa, 143 proteins were differentially expressed in diabetics and nondiabetics. An enrichment analysis of this signature pointed to mitochondria, ribosome, and translation. Only six proteins were upregulated by diabetes both in tumor and mucosa, of which five were mitochondrial proteins. Differential expression in diabetic versus nondiabetic mucosa was confirmed for MRPL53, MRPL18, and TIMM8B. Higher levels of MRPL18, TIMM8B, and EIF1A were also found in normal colon epithelial cells exposed to high-glucose conditions. We conclude that T2DM is associated with specific molecular changes in the normal mucosa of CC patients, consistent with field of cancerization in a diabetic environment. The mitochondrial protein signature identifies a potential therapeutic target that could underlie the higher risk of CC in diabetics.

SUBMITTER: Del Puerto-Nevado L

PROVIDER: S-EPMC6717745 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Del Puerto-Nevado Laura L Santiago-Hernandez Aranzazu A Solanes-Casado Sonia S Gonzalez Nieves N Ricote Marta M Corton Marta M Prieto Isabel I Mas Sebastian S Sanz Ana Belen AB Aguilera Oscar O Gomez-Guerrero Carmen C Ayuso Carmen C Ortiz Alberto A Rojo Federico F Egido Jesus J Garcia-Foncillas Jesus J Minguez Pablo P Alvarez-Llamas Gloria G

Molecular oncology 20190727 9

Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of cancer, including colon cancer (CC). However, we recently reported no influence of T2DM on CC prognosis, suggesting that any effect might be at the early stages of tumor development. We hypothesized that T2DM may create an environment in the healthy tissue, which acts as a carcinogenesis driver in agreement with the field of cancerization concept. Here, we focused on early carcinogenesis by analyzing paired tumor and n ...[more]

PMID: 31199051

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Project description:AimTo investigate the mechanistic action of brewers' rice in regulating the Wnt/nuclear factor-kappa B (NF-κB)/Nrf2-signaling pathways during colon carcinogenesis in male Sprague-Dawley rats.MethodsMale Sprague-Dawley rats were randomly divided into the following five groups (six rats in each group): (G1) normal, (G2) azoxymethane (AOM) alone, (G3) AOM + 10% (weight (w)/weight (w)) brewers' rice, (G4) AOM + 20% (w/w) brewers' rice, and (G5) AOM + 40% (w/w) brewers' rice. They were intraperitoneally administered 15 mg/kg body weight of AOM in saline once weekly over a two-week period and treated with an American Institute of Nutrition (AIN)-93G diet containing 10%, 20%, and 40% (w/w) brewers' rice. The mRNA levels of glycogen synthase kinase 3β (GSK3β), β-catenin, key inflammation markers, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1)-dependent transcriptional activity were assessed by quantitative real-time polymerase chain reaction analyses. The colon superoxide dismutase, malondialdehyde, and nitric oxide levels were also analyzed to assess the antioxidant effect of these treatments. The results were analyzed using one-way analysis of variance (ANOVA), and a P value of < 0.05 was considered significant.ResultsThe overall analyses demonstrated that the dietary administration of brewers' rice in AOM-induced rat colon carcinogenesis resulted in the transcriptional upregulation of GSK3β, inducible nitric oxide synthase (iNOS), Nrf2, and HO-1. We discovered that the dietary administration of brewers' rice downregulated the β-catenin and NF-κB mRNA levels. A significant reduction in β-catenin expression was found in the groups administered with 20% (0.611 ± 0.034) and 40% (0.436 ± 0.045) (w/w) brewers' rice compared with that of the group treated with AOM alone (1.000 ± 0.064) (P < 0.05). The NF-κB expression was significantly lower between the AOM-alone group (1.000 ± 0.048) and those groups fed with diets containing 10% (w/w) brewers' rice (0.255 ± 0.022), 20% (w/w) brewers' rice (0.450 ± 0.045), or 40% (w/w) brewers' rice (0.541 ± 0.027) (P < 0.05). Brewers' rice improved the antioxidant levels, indicating that brewers' rice can enhance effective recovery from oxidative stress induced by AOM.ConclusionOur results provide evidence that brewers' rice can suppress colon cancer via the regulation of Nrf2 expression and the inhibition of the Wnt/NF-κB signaling pathways.

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

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

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