Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

Yang, Juhong; Nishihara, Reiko; Zhang, Xuehong; Ogino, Shuji; Qian, Zhi Rong

doi:10.1016/j.jdiacomp.2017.04.012

Cited by 40 publications

(33 citation statements)

References 153 publications

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“…In any case, the controversies generated by the different observational studies have strengthened the need to study the molecular mechanisms behind a possible association between both diseases, today still unclear. In this context, some authors have proposed several metabolic pathways, such as the insulin pathway or oxidative stress, as important players linking diabetes to promotion of tumor development or metastasis (Ikemura et al, 2013;Teng et al, 2016;Yang et al, 2017). However, there is very limited information derived from patient samples supporting these evidences.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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The potential involvement of type 2 diabetes mellitus (T2 DM ) as a risk factor for colon cancer ( CC ) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2 DM ‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2 DM . We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD / YAP ‐ TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2 DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD / YAP ‐ TAZ complex as a potential driver.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…AMPK, Sirt1, and mTOR signaling) and the gut microbiome. 37,38 Therefore, any mediation we observed does not necessarily identify C-peptide, sOB-R, and adiponectin as the causal agents driving associations between adiposity and CRC risk, but rather more likely represents the possible importance of metabolism and insulin response as key pathways linking adiposity with CRC risk. Notably, we observed stronger results for the joint mediating effects of the metabolic biomarkers than when each of these biomarkers was considered alone, suggesting that the 1 Per one-unit increase in the interquartile range of each adiposity measure (body mass index: 3.6 kg/m 2 ; adult weight gain: 10.4 kg; waist circumference: 11.4 cm).…”

Section: Discussionmentioning

confidence: 93%

“…However, the biological mechanisms behind metabolism and CRC are complex, and may involve several pathways, such as energy sensing pathways (e.g. AMPK, Sirt1, and mTOR signaling) and the gut microbiome . Therefore, any mediation we observed does not necessarily identify C‐peptide, sOB‐R, and adiponectin as the causal agents driving associations between adiposity and CRC risk, but rather more likely represents the possible importance of metabolism and insulin response as key pathways linking adiposity with CRC risk.…”

Section: Discussionmentioning

confidence: 93%

Mediation of associations between adiposity and colorectal cancer risk by inflammatory and metabolic biomarkers

Petimar

Tabung

Valeri

et al. 2019

Intl Journal of Cancer

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Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (ORTE) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; ORNIE) or through paths independent of these biomarkers (natural direct effect; ORNDE) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow‐up Study, a prospective cohort of male health professionals. A one‐interquartile range (IQR) increase in body mass index (3.6 kg/m2) was associated with an ORTE of 1.40 (95% CI: 1.13, 1.73), which decomposed into an ORNIE of 1.26 (95% CI: 0.97, 1.52) and an ORNDE of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4 kg; ORTE = 1.32 [95% CI: 1.06, 1.64]; ORNIE = 1.47 [95% CI: 1.01, 1.81]; ORNDE = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk.

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“…T2DM has been demonstrated to increase CRC aggressiveness and mortality (6,7). The key molecular mechanisms by which T2DM increases the incidence or worsens the prognosis of patients with CRC are associated with nutrient-sensing pathways coupling energy metabolism to signals of cell growth and survival, which are often dysregulated in diabetes, and may be important contributors to cancer development in patients with diabetes (8). The pathophysiology of T2DM involves enhanced oxidative stress induced by high plasma glucose, lipid and cytokine levels, which can trigger endoplasmic reticulum (ER) stress (9).…”

Section: Introductionmentioning

confidence: 99%

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

et al. 2019

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There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.

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Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

Cited by 40 publications

References 153 publications

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

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

Mediation of associations between adiposity and colorectal cancer risk by inflammatory and metabolic biomarkers

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

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