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      Adipose tissue inflammation and VDR expression and methylation in colorectal cancer

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          Abstract

          Background

          Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC.

          Methods

          Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group.

          Results

          Adipose tissue NFκB1, IL6, and IL1B gene expression were higher in the CRC subjects than in the control subjects. 25(OH)D correlated negatively with NFκB1 and CRP. In turn, CRP correlated positively with NFκB1, IL6, IL1B, and VDR gene expression as well as NFκB1 that correlated positively with IL6 and IL1B. DNMT3A mRNA was negatively correlated with serum 25(OH)D and positively correlated with VDR DNA methylation. VDR DNA methylation at position 4 had lower levels in the CRC group. Global NFκB1 methylation at dinucleotide 3 was lower in the CRC group.

          Conclusion

          Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue VDR expression in CRC may, at least in part, mediate this relationship by modifying adipose tissue DNA methylation and promoting inflammation.

          Electronic supplementary material

          The online version of this article (10.1186/s13148-018-0493-0) contains supplementary material, which is available to authorized users.

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          Most cited references 27

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          Adipose tissue, adipokines, and inflammation.

          White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.
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            Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.

            Vitamin D has potent anticancer properties, especially against digestive-system cancers. Many human studies have used geographic residence as a marker of solar ultraviolet B and hence vitamin D exposure. Here, we considered multiple determinants of vitamin D exposure (dietary and supplementary vitamin D, skin pigmentation, adiposity, geographic residence, and leisure-time physical activity-to estimate sunlight exposure) in relation to cancer risk in the Health Professionals Follow-Up Study. Among 1095 men of this cohort, we quantified the relation of these six determinants to plasma 25-hydroxy-vitamin D [25(OH)D] level by use of a multiple linear regression model. We used results from the model to compute a predicted 25(OH)D level for each of 47,800 men in the cohort based on these characteristics. We then prospectively examined this variable in relation to cancer risk with multivariable Cox proportional hazards models. From 1986 through January 31, 2000, we documented 4286 incident cancers (excluding organ-confined prostate cancer and nonmelanoma skin cancer) and 2025 deaths from cancer. From multivariable models, an increment of 25 nmol/L in predicted 25(OH)D level was associated with a 17% reduction in total cancer incidence (multivariable relative risk [RR] = 0.83, 95% confidence interval [CI] = 0.74 to 0.92), a 29% reduction in total cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45% reduction in digestive-system cancer mortality (RR = 0.55, 95% CI = 0.41 to 0.74). The absolute annual rate of total cancer was 758 per 100,000 men in the bottom decile of predicted 25(OH)D and 674 per 100,000 men for the top decile; these respective rates were 326 per 100,000 and 277 per 100,000 for total cancer mortality and 128 per 100,000 and 78 per 100,000 for digestive-system cancer mortality. Results were similar when we controlled further for body mass index or physical activity level. Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.
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              Vitamin D signalling in adipose tissue.

              Vitamin D deficiency and the rapid increase in the prevalence of obesity are both considered important public health issues. The classical role of vitamin D is in Ca homoeostasis and bone metabolism. Growing evidence suggests that the vitamin D system has a range of physiological functions, with vitamin D deficiency contributing to the pathogenesis of several major diseases, including obesity and the metabolic syndrome. Clinical studies have shown that obese individuals tend to have a low vitamin D status, which may link to the dysregulation of white adipose tissue. Recent studies suggest that adipose tissue may be a direct target of vitamin D. The expression of both the vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes has been shown in murine and human adipocytes. There is evidence that vitamin D affects body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation. Some recent studies demonstrate that vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue. Therefore, vitamin D deficiency may compromise the normal metabolic functioning of adipose tissue. Given the importance of the tissue in energy balance, lipid metabolism and inflammation in obesity, understanding the mechanisms of vitamin D action in adipocytes may have a significant impact on the maintenance of metabolic health. In the present review, we focus on the signalling role of vitamin D in adipocytes, particularly the potential mechanisms through which vitamin D may influence adipose tissue development and function.
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                Author and article information

                Contributors
                +34 951032648 , mer.cp@hotmail.com
                +34 951032648 , mmacias.manuel@gmail.com
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                25 April 2018
                25 April 2018
                2018
                : 10
                Affiliations
                [1 ]ISNI 0000 0001 2298 7828, GRID grid.10215.37, 1Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, , Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, ; Málaga, Spain
                [2 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), ; Madrid, Spain
                [3 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), , Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), ; Santiago de Compostela, Spain
                [4 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), ; Madrid, Spain
                [5 ]ISNI 0000 0000 9788 2492, GRID grid.411062.0, Unidad de Gestión Clínica de Oncología Intercentros Hospital Universitario Virgen de la Victoria, ; Málaga, Spain
                Article
                493
                10.1186/s13148-018-0493-0
                5921388
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: CIBER ISCIII
                Award ID: CB06/03/0018
                Funded by: ISCIII
                Award ID: PI11/01661, PI15/0114
                Funded by: Co-financed by the European Regional Development Fund
                Award ID: FEDER
                Funded by: FPU
                Award ID: 13/04211
                Funded by: Nicolas Monardes Programme from the “Servicio Andaluz de Salud, Junta de Andalucia
                Award ID: C-0029-2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Genetics

                vitamin d, vdr, dna methylation, low-grade inflammation, colorectal cancer, adipose tissue

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