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.

中文翻译：

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糖尿病介导的结肠粘膜癌变的促进与线粒体功能障碍有关。

2型糖尿病（T2DM）与包括结肠癌（CC）在内的癌症风险增加相关。但是，我们最近报道T2DM对CC预后没有影响，表明任何影响都可能在肿瘤发展的早期。我们假设T2DM可以在健康组织中创造一个环境，该环境可以作为致癌驱动程序，与癌症概念领域相符。在这里，我们通过分析来自同一患者的配对肿瘤和正常结肠粘膜样品，着重于早期致癌作用。CC和配对粘膜的蛋白质组通过等压标记质谱定量分析了28位个体（12位糖尿病患者和16位非糖尿病患者）中的蛋白质。与非糖尿病患者相比，在3076种已鉴定蛋白中，有425种在糖尿病患者的肿瘤中差异表达。在邻近的黏膜中 在糖尿病和非糖尿病患者中差异表达了143种蛋白质。对该特征的富集分析指出线粒体，核糖体和翻译。糖尿病和粘膜中只有六种蛋白被上调，其中五种是线粒体蛋白。证实了MRPL53，MRPL18和TIMM8B在糖尿病和非糖尿病粘膜中的差异表达。在暴露于高葡萄糖条件下的正常结肠上皮细胞中也发现了更高水平的MRPL18，TIMM8B和EIF1A。我们得出的结论是，T2DM与CC患者正常黏膜中的特定分子变化有关，这与糖尿病环境中的癌变领域一致。线粒体蛋白特征识别出潜在的治疗目标，该潜在治疗目标可能是糖尿病患者较高CC风险的基础。