Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Puerto‐Nevado, Laura del; Mínguez, Pablo; Cortón, Marta; Solanes-Casado, Sonia; Prieto, I.; Mas, Sebastián; Sanz, Ana B.; Gónzález-Alonso, Paula; Villaverde, Cristina; Portal‐Núñez, Sergio; Aguilera, Óscar; Gómez-Guerrero, Carmen; Esbrit, Pedro; Vivanco, Fernando; González, Nieves; Ayuso, Carmen; Ortíz, Alberto; Rojo, Federico; Egido, Jesús; Alvarez-Llamas, Gloria; Garcı́a-Foncillas, Jesús

doi:10.1002/1878-0261.12438

Cited by 13 publications

(16 citation statements)

References 60 publications

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“…In agreement with these evidences, we recently showed how T2DM could promote a precancer state by means of signaling pathways exclusively activated in diabetic normal mucosa (Del Puerto‐Nevado et al , ). Molecular changes specifically occurring in the normal colon mucosa of diabetic patients would thus explain their higher risk of CC development.…”

Section: Introductionsupporting

confidence: 72%

“…Specifically, in colorectal cancer, several authors have reported evidences regarding a ‘field effect’ in the normal mucosa surrounding the tumor characterized by changes in methylation pattern, chromosomal instability, copy number alterations, or even in Warburg metabolism. Among the potential mechanisms responsible for this effect, T2DM has been proposed as a factor for FC in in vitro approaches (Del Puerto‐Nevado et al , ; Rubin, ; Slaughter et al , ). Gene and protein deregulation has been reported in such ‘normal’ tissue (Guo et al , ; Sanz‐Pamplona et al , ), and gradual signatures were correlated with distance to the tumor.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Introductionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Fumarate accumulation can trigger oncogenesis and drive transformation, even without genetic alteration [70]. Diabetic patients had altered YAP/TAZ-TEAD signaling in normal mucosa, which play key roles in the initiation and field cancerization of the colon compared to non-diabetic patients [71]. Hyperglycemia also causes inflammation [72] via increasing obesity [73], gut permeability [74], and LDL levels in humans [75].…”

Section: Hyperglycemia and Risk Factors For Cancermentioning

confidence: 99%

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

Ramteke

Deb

Shepal

et al. 2019

Cancers

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Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic transformation is hyperglycemia. Epidemiologically too, lifestyle patterns resulting in high blood glucose level, with or without the role of insulin, are more often correlated with cancer risk, progression, and mortality. The two conditions recurrently exist in comorbidity, and their interplay has rendered treatment regimens more challenging by restricting the choice of drugs, affecting surgical consequences, and having associated fatal complications. Limited comprehensive literature is available on their correlation, and a lack of clarity in understanding in such comorbid conditions contributes to higher mortality rates. Hence, a critical analysis of the elements responsible for enhanced mortality due to hyperglycemia-cancer concomitance is warranted. Given the lifestyle changes in the human population, increasing metabolic disorders, and glucose addiction of cancer cells, hyperglycemia related complications in cancer underline the necessity for further in-depth investigations. This review, therefore, attempts to shed light upon hyperglycemia associated factors in the risk, progression, mortality, and treatment of cancer to highlight important mechanisms and potential therapeutic targets.

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“…SW480 cells were cultured at 37°C, in 5% CO 2 cell culture incubator. SW480 cells were divided into two groups, one group was cultured using conventional medium, and the other group was cultured using medium supplemented with 25 mM glucose ( 24 , 25 ).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of miR‑98 inhibiting tumor proliferation and invasion by targeting IGF1R in diabetic patients combined with colon cancer

Liu

Zhou

et al. 2020

Oncol Lett

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Expression level of miR-98 in diabetic colon cancer (CRC) tissues and the regulation mechanism of colon cancer cell proliferation and invasion ability were studied. Forty patients with type 2 diabetes mellitus complicated with colon cancer, 40 colon cancer patients, and 40 patients with diabetic colonoscopy were enrolled between January 2017 and January 2018. Real-time quantitative PCR was used to detect the expression level of miR-98. After SW480 cells were transfected with miR-98 mimics or control simulants, the proliferation of cancer cells was detected by MTT assay, and the invasion ability of cancer cells was detected by Transwell cell invasion assay. The dual luciferase assay was used to detect the binding relationship between miR-98 and IGF1R. Western blot analysis was used to detect the expression of IGF1R protein in tumor tissues of patients with diabetes mellitus and colon cancer. Compared with diabetic patients, the expression level of miR-98 was decreased in colon cancer patients. Compared with tumor tissues of colon cancer patients, the expression level of miR-98 was significantly decreased in diabetic colon cancer tissues. Compared with the commonly cultured colon cancer SW480 cells, the expression level of miR-98 was significantly decreased in SW480 cells cultured under high glucose conditions. Increased expression of miR-98 inhibits colon cancer cell proliferation and invasion. miR-98 can target and bind to IGF1R and inhibit its expression level. IGF1R is upregulated in diabetic colon cancer tissue. miR-98 inhibits proliferation and invasion of diabetic colon cancer by targeting IGF1R. The expression level of miR-98 in diabetic colon cancer tissues is lower than that in colon cancer tissues. miR-98 can inhibit the proliferation and invasion of colon cancer cells by targeting the target gene IGF1R. miR-98 may be a potential biological target for the treatment of patients with diabetes and colon cancer.

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Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Cited by 13 publications

References 60 publications

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

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

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

Mechanism of miR‑98 inhibiting tumor proliferation and invasion by targeting IGF1R in diabetic patients combined with colon cancer

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