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.

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

“…Many different aspects of mitochondrial biology directly influence tumorigenesis, including alterations to cell death pathways, mitochondrial dynamics, mitochondrial biogenesis and mTOR signalling, and oxidative stress [10]. A significant number of components of the mitochondrial import machineries are overexpressed in a variety of different cancers, including subunits of the TOM complex (Tom20, Tom40, Tom7 and Tom70) [186,[188][189][190][191][192], the TIM23 complex (Tim17a, Mortalin, Magmas, Tim50 and Tim23) [186,[193][194][195][196][197][198][199][200][201][202][203][204][205][206][207], the TIM22 complex (Tim22, AGK) [186,[208][209][210][211][212][213][214][215][216][217], the small Tim chaperones (Tim8a, Tim8b, Tim9, Tim13) [186,[218][219][220] and Mia40 [221,222]. In addition, two variants of Tim44 (C925A and G1274A) have been identified in oncocytic thyroid carcinomas [223].…”

TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

“…Reduced levels were observed here, meanwhile its product, glutamic acid, was increased. We have previously related a mitochondrial dysfunction in diabetic conditions [46] and in non-diabetic CKD patients, the TCA cycle pathway being the most significantly altered [47]. α-Ketoglutaric acid was found to be markedly reduced, so too was the expression of regulating genes (OGDH) in kidney biopsies.…”

Whole‑genome identification and systematic analysis of lncRNA‑mRNA co‑expression profiles in patients with cutaneous basal cell carcinoma

“…This lncRNA has not been studied, but the co-expression network demonstrated that it has a co-expression relationship with six mRNAs, TICAM1, USMG5, COX7A2, FBXO10, ATP5E and TIMM8B. Notably, all these mRNAs are reported to be associated with mitochondrial dysfunction and glucose metabolism (35)(36)(37)(38)(39)(40)(41). In the co-expression network of the present study, lncRNA XR_428612.1 was positively correlated with TIR domain-containing adaptor molecule-1 (TICAM1).…”

“…TIMM8B, a mitochondrial ribosomal protein (MRP), has been reported to be upregulated in colon mucosa carcinogenesis mediated by diabetes ( 28 ). MRPs may be affected by glucose metabolism and participate in proliferation, metastasis, or cellular migration in malignancies ( 38 ). In addition, diabetes-associated protein in insulin-sensitive tissues (DAPIT) encoded by USMG5 ( 39 ), ATP synthase epsilon subunit (ATP5E) and cytochrome c oxidase subunit 7A2 (COX7A2) are partial components of ATP synthase and participate in the interconversion of mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, both of which are sources of ATP ( 40 , 41 ).…”